The FEBS Journal - 2020 - Vanderhaeghen - Hypoxia Inducible Factors in Metabolic Reprogramming During Sepsis

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REVIEW ARTICLE
Hypoxia-inducible factors in metabolic reprogramming

during sepsis
Tineke Vanderhaeghen1,2 , Jolien Vandewalle1,2 and Claude Libert1,2
1 Center for Inflammation Research, VIB, Ghent, Belgium
2 Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
Keywords Sepsis is a highly heterogeneous syndrome that is caused by an imbalanced

HIF; hypoxia; metabolism; sepsis host response to infection. Despite huge investments, sepsis remains a con-
temporary threat with significant burden on health systems. Vascular dys-
Correspondence
function and elevated oxygen consumption by highly metabolically active
C. Libert, Department of Biomedical
Molecular Biology, VIB-UGent Center for immune cells result in tissue hypoxia during inflammation. The transcrip-
Inflammation Research, Ghent University, tion factor hypoxia-inducible factor-1a (HIF1a), and its family members,
Technologiepark 71, Ghent 9052, Belgium plays an important role in cellular metabolism and adaptation to cellular
Tel: +32 (0) 9 33 13721 stress caused by hypoxia. In this review, we discuss the role of HIF in sep-
E-mail: Claude.Libert@irc.vib-ugent.be sis. We show possible mechanisms by which the inflammatory response
activated during sepsis affects the HIF pathway. The activated HIF path-
Tineke Vanderhaeghen and Jolien
way in turn changes the metabolism of both innate and adaptive immune
Vandewalle shared first authorship.
cells. As HIF expression in leukocytes of septic patients can be directly
(Received 27 September 2019, revised 20 linked with mortality, we discuss multiple ways of interfering with the HIF
December 2019, accepted 20 January 2020) signaling pathway.
doi:10.1111/febs.15222
Introduction
Sepsis is a major healthcare problem worldwide. It is [1]. It is estimated that worldwide more than 19 mil-
the most common cause of admission to the intensive lion people are affected by sepsis each year. Mortality
care unit (ICU), the leading cause of mortality in the rates range from 28% for sepsis patients to 46% in
ICU, and the leading cause of mortality in children case of septic shock [1]. In 2016, the definition of
Abbreviations
2-ME, 2-methoxyestradiol; 3,4-DHB, 3,4-dihydroxybenzoate; AA, amino acid; ARD1, arrest-defective 1; ARNT, aryl hydrocarbon receptor
nuclear translocator; Asn, asparagine; bHLH-PAS, basic helix-loop-helix Pern-Arnt-Sim; CBP, CREB binding protein; CD, Crohn’s disease;
CHIP, carboxyl terminus of Hsp70-interacting protein; CIRBP, cold-inducible RBP; CLP, cecal ligation and puncture; CPEB, cytoplasmic
polyadenylation element binding protein; C-TAD, C-terminal transactivation domain; DC, dendritic cell; DHMP, 5,7-dihydroxy-8-
methoxyflavone; DMOG, dimethyloxallyl glycine; EPO, erythropoietin; Fe2+, Iron; FIH, factor inhibiting HIF1; G6PD, glucose-6-phosphate
dehydrogenase; GSK3, glycogen synthase kinase 3; HAF, hypoxia-associated factor; HIF, hypoxia-inducible factor; HK1, hexokinase; HRE,
hypoxia-responsive element; Hsp, heat-shock protein; HuR, Hu antigen R; IBD, inflammatory bowel disease; ICU, intensive care unit; ID,
inhibitory domain; IECs, intestinal epithelial cells; IPAS, inhibitory PAS domain protein; IRE, iron-responsive element; IRP, iron regulatory
protein; LDH, lactate dehydrogenase; LPS, lipopolysaccharide; MAPK, mitogen-activated protein kinase; miR, microRNA; NLS, nuclear
localization signal; NO, nitric oxide; N-TAD, N-terminal transactivation domain; ODDD, oxygen-dependent degradation domain; PDK1,
pyruvate dehydrogenase kinase; PFK1, phosphofructokinase-1; PHD, prolyl hydroxylase; Pro, proline; PTB, polypyrimidine tract binding
protein; pVHL, von Hippel-Lindau protein; RACK1, receptor of activated protein kinase C; RBM38, RNA binding motif protein 38; RBP, RNA
binding protein; ROS, reactive oxygen species; SIRS, systemic inflammatory response syndrome; SpO2, oxygen saturation level; Treg,
regulatory T cell; TTP, tristetraprolin; UC, ulcerative colitis; UTR, untranslated region; VEGF, vascular endothelial growth factor; WHO, World
Health Organization; YB-1, Y-box binding protein 1; a-KG, a-ketoglutarate.
1478 The FEBS Journal 287 (2020) 1478–1495 ª 2020 Federation of European Biochemical Societies
17424658, 2020, 8, Downloaded from https://febs.onlinelibrary.wiley.com/doi/10.1111/febs.15222 by CAPES, Wiley Online Library on [20/12/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
T. Vanderhaeghen et al. The role of HIF in sepsis
sepsis was revised since previous definitions had been degradation domain (ODDD) and two transactivation
focusing too much on inflammation and on the sys- domains are present: the N-terminal transactivation
temic inflammatory response syndrome (SIRS) criteria, domain (N-TAD) and the C-terminal transactivation
which appeared to be inadequately specific for sepsis. domain (C-TAD). The N-TAD has an overlap with
Indeed, sepsis was characterized as a systemic pro-in- the ODDD and is responsible for the stability and the
flammatory response, but many immunomodulatory target gene specificity [7,9]. The C-TAD interacts with
therapies failed to show any protection in clinical tri- co-activators; for example, CREB binding protein
als. The new Sepsis-3 definition of 2016 describes sep- (CBP) and p300 are required for full HIF activity and
sis as a life-threatening organ dysfunction resulting regulate the expression of most HIF target genes [10].
from a dysregulated host response to infection [2]. Finally, there are two nuclear localization signals, N-
Furthermore, the latest septic shock definitions NLS and C-NLS, which direct the protein to the
acknowledge the importance of metabolic changes dur- nucleus [11].
ing sepsis [3]. A large proteomic and metabolic screen HIF2a has a high structural similarity with HIF1a,
on plasma of sepsis patients identified that glycolysis, but they differ in their transactivation domains. Differ-
gluconeogenesis, and the citric acid cycle differed ences in the N-TAD lead to target gene specificities of
prominently between sepsis survivors and nonsurvivors HIF1a and HIF2a, whereas the C-TAD promotes the
[4]. Levels of lactate, an indicator of cellular and meta- expression of their common target genes [12]. HIF3a is
bolic stress, can be directly correlated with disease known as the dominant-negative regulator of the HIF
severity, morbidity, and mortality in sepsis [5]. In pathway. It shows a high structural similarity with
2017, the World Health Organization (WHO) has rec- HIF1a and HIF2a in the bHLH and PAS domains;
ognized sepsis as a global health priority issue. Despite however, the C-TAD is absent [13]. HIF3a can bind
the fact that sepsis has been known since the times of HIF1b, hereby competing with HIF1a and HIF2a.
Hippocrates and that enormous investments have been Also, HIF3a reduces the expression levels of HIF1a
made in sepsis research, no new effective drugs have and HIF2a, leading to a decreased expression of
penetrated to the bedside. Today, the management of HIF1a and HIF2a target genes [14]. A splice variant
sepsis relies on antimicrobial treatment and organ sup- of HIF3a, known as the inhibitory PAS domain pro-
portive therapies. However, antibiotic resistance is a tein (IPAS), is able to dimerize with HIF1a and dis-
huge concern and this might even contribute to the rupt the binding of HIF1a with the hypoxia-
increased rates of sepsis, next to the aging of the world responsive elements (HREs) of its target genes [15].
population. Even if patients survive sepsis, many of This demonstrates that a negative feedback mechanism
them never fully recover, and these patients show sub- by HIF3a/IPAS may be present for HIF regulation.
stantial and persistent cognitive impairment and func- Several animal knockout models have shown the
tional disability [6]. Innovative approaches targeting importance of HIF1a, HIF2a, and HIF3a during
sepsis in combination with appropriate antibiotics are development. HIF1a and HIF2a knockout mice are
thus a huge unmet need of today’s medical practice. not viable. The absence of HIF1a during embryonic
development leads to defects in cardiovascular devel-
opment, an overwhelming degree of cell death and
The structure and physiology of
neural tube defects causing death at embryonic day
hypoxia-inducible factors
(E)10.5 [16]. Deficiency of HIF2a causes severe abnor-
Hypoxia-inducible factors (HIFs) are transcription fac- malities in the remodeling of the primary vascular net-
tors that are known to be the master regulators of work, leading to death in utero between E9.5 and
oxygen homeostasis and are important in development, E13.5 [17]. In contrast to HIF1a- and HIF2a-deficient
physiology, and disease. They belong to the basic mice, HIF3a knockout mice are viable. However, the
helix-loop-helix Per-Arnt-Sim (bHLH-PAS) transcrip- absence of HIF3a leads to impaired heart and lung
tion factor superfamily and consist of heterodimers development during embryonic and neonatal stages
containing an a- and b-subunit (Figure 1). The a-sub- [18].
units are known to be oxygen-sensitive, as they accu- The constitutively expressed b-subunit, also known
mulate in hypoxic conditions. Three a-subunits are as the aryl hydrocarbon receptor nuclear translocator
found in mammals, namely HIF1a, HIF2a, and (ARNT), is not affected by hypoxia [7,8]. HIF1b also
HIF3a [7,8]. contains a bHLH domain, PAS domain, and TAD
HIF1a contains a bHLH and a PAS domain, neces- domains. However, no ODDD is present, which leads
sary for DNA binding and heterodimerization, respec- to the constitutive expression of HIF1b in an oxygen-
tively. Besides these domains, an oxygen-dependent independent way [19].
The FEBS Journal 287 (2020) 1478–1495 ª 2020 Federation of European Biochemical Societies 1479
The role of HIF in sepsis T. Vanderhaeghen et al.
Fig. 1. Schematic presentation of the structure of hypoxia-inducible factors (HIFs). HIFs are basic helix-loop-helix Per-Arnt-Sim (bHLH-PAS)
transcription factors consisting of heterodimers with an a- and b-subunit. HIF1a contains a bHLH and a PAS domain, required for DNA
binding and heterodimerization, respectively. Also, an oxygen-dependent degradation domain (ODDD) and two transactivation domains (N-
TAD and C-TAD) are present. The N-TAD is responsible for the stability and target gene specificity and overlaps with the ODDD. The C-TAD
interacts with co-activators activating gene transcription. HIF2a shows high structural similarity with HIF1a, but they differ in their
transactivation domains. HIF3a is known as the dominant-negative regulator and shows a high structural similarity with HIF1a and HIF2a in
the bHLH and PAS domains. However, the C-TAD is absent. HIF1b is constitutively expressed due to the absence of the ODDD and forms
heterodimers with the a-subunits.
HIF protein regulation In the presence of low oxygen concentrations, or in

the absence of their cofactors Fe2+, a-KG or vitamin
In oxygenated conditions, the HIFa proteins are
C, PHDs are inactivated and are unable to hydroxy-
constantly produced by transcription and translation.
late the Pro residues. The a-subunits are then stabi-
However, due to a half-life of 5 min [20], it is
lized, dimerize with HIF1b, and translocate to the
directly degraded by the 26S proteasome (Figure 2).
nucleus. Along with recruitment of CBP/p300 as cofac-
Under normoxic conditions, HIFa proteins are post-
tors, the heterodimer will bind to the HREs, contain-
translationally modified by prolyl hydroxylases
ing an invariant core sequence RCGTG (R: A/G) [28],
(PHD) namely PHD1, PHD2, or PHD3. The activity
for activation of their target genes [19]. Recently,
of a PHD is oxygen-dependent and relies on the
Smythies et al. [29] showed that HIF1 will bind more
presence of oxygen, iron (Fe2+), a-ketoglutarate (a-
closely to the promotor of the target gene, while HIF2
KG, also known as 2-oxoglutarate), and ascorbic
more frequently binds enhancer, distant from the
acid (also known as vitamin C) [19]. PHD2 con-
promotors.
tributes to the regulation of HIF1a, while the
expression of HIF2a is regulated by PHD1 and
PHD3 [21–23]. The PHDs hydroxylate proline (Pro)
Other mechanisms of HIF protein regulation
residues (Pro 402 and 564 for HIF1a and Pro 405
and 531 for HIF2a) present in the ODDD, which Hypoxia-associated factor (HAF) is able to regulate
leads to the binding of the von Hippel-Lindau pro- the HIF1a protein levels in an oxygen and pVHL-in-
tein (pVHL). Then, the elongin-C/elongin-B/cullin-2 dependent manner. It is known to be an E3-ubiquitin
E3-ubiquitin-ligase complex is recruited, targeting the ligase that will bind and ubiquitinate HIF1a targeting
HIFa protein for degradation by the 26S proteasome it for proteasomal degradation, irrespective of the oxy-
[24,25]. gen concentration [30]. Koh et al. [31] also showed
A second oxygen-dependent mechanism that is used that HAF is able to bind HIF2a, at a different site
for the regulation of HIFa under normoxic conditions than HIF1a, thereby promoting the stabilization and
is based on the hydroxylation of an asparagine (Asn) transactivation capacity of HIF2a.
residue (Asn 803 for HIF1a and Asn 851 for HIF2a) Another mechanism that can be used for the decay
in the C-TAD by the factor inhibiting HIF1 (FIH). of HIF1a is based on the heat-shock protein 70
This hydroxylation prevents the interaction of the C- (Hsp70)/carboxyl terminus of Hsp70-interacting pro-
TAD with co-activators and inhibits the transcrip- tein (CHIP) complex. Hsp70 will bind to HIF1a,
tional activity of HIFa [26,27]. which will lead to the recruitment of CHIP, an E3-
Fig. 2. Hypoxia-inducible factor activity

under normoxic and hypoxic conditions.
Under normoxic conditions, prolyl
hydroxylases (PHDs) hydroxylate proline
residues present in the oxygen-dependent
degradation domain (ODDD) leading to the
binding of the von Hippel-Lindau protein
(pVHL). Subsequently, the a-subunit is
ubiquitinated and degraded by the 26S
proteasome. Next to PHDs, the factor
inhibiting HIF1 (FIH) hydroxylates an
asparagine residue present in the C-terminal
transactivation domain (C-TAD). This
prevents the interaction of the C-TAD with
co-activators inhibiting gene transcription. In
low oxygen concentrations, PHDs are
inactivated and the a-subunits are stabilized,
dimerize with HIFb components, and
translocate to the nucleus. After
recruitment of CBP/p300 as co-activators,
the heterodimer binds to the hypoxia-
responsive elements (HREs) activating gene
transcription.
ubiquitin ligase, ubiquitination of HIF1a followed by conserved in HIF1a and HIF2a, but not in HIF3a.
proteasomal degradation. Unlike HAF, the Hsp70/ ARD1-mediated acetylation favors the interaction of
CHIP complex cannot regulate HIF2a protein stability HIF1a with pVHL and HIF1a ubiquitination, leading
[32]. to proteasomal degradation [34]. However, another
A third manner that is used for the regulation of study by Arnesen et al. [35] shows that ARD1 is able
HIF1a protein levels is based on Hsp90 and the recep- to bind HIF1a, but does not acetylate and destabilize
tor of activated protein kinase C (RACK1). Hsp90 will the a-subunit. More recently, Geng et al. [36] observed
protect HIF1a degradation in an O2 independent man- that p300 is able to specifically acetylate K709, leading
ner by binding to the PAS domain, thereby protecting to an increased protein stability of HIF1a and
HIF1a from proteasomal degradation. However, Liu decreased polyubiquitination, both in normoxia and
et al. showed that RACK1 can also bind to the PAS hypoxia.
domain, hereby competing with Hsp90. Binding of Phosphorylation is also an important post-transla-
RACK1 leads to the recruitment of elongin-C and tional modification of the HIF proteins. Under
elongin-B of the E3-ubiquitin ligase complex, leading hypoxia and due to nonhypoxic stimuli, such as nitric
to proteasomal degradation of HIF1a in a similar way oxide (NO) and insulin, the glycogen synthase kinase 3
of pVHL, however being O2 independent [33]. (GSK3) acts directly on HIF1a by phosphorylating
serine residues present in the ODDD and N-TAD.
This leads to the recruitment of SCF complex (Skp1,
Post-translational modifications
Cul1, and F-box protein) containing the F-box protein
Next to hydroxylation and ubiquitination, acetylation Fbw7, a multi-subunit of E3 ubiquitin ligases, and the
is a third manner to induce post-translational modifi- degradation of HIF1a [37–39]. p38, a MAPK kinase,
cations to the HIFa proteins. Jeong et al. reported is able to phosphorylate amino acids (AAs) in the inhi-
that an acetyltransferase named arrest-defective 1 bitory domain (ID), present between the N-TAD and
(ARD1) is able to acetylate Lysine 532 (K532) present C-TAD, and contributes to the stabilization of HIF1a
in the ODDD of HIF1a. This K532 residue is [40]. Other studies have reported that phosphorylation
Table 1. Overview of the post-translational modifications of the HIFa subunits.
Molecule Post-translational modification HIF target protein References
PHD Hydroxylation of Pro402 and Pro564 in ODDD leading to HIF1a ↓ [24,25]

ubiquitination
Hydroxylation of Pro405 and Pro531 in ODDD leading to HIF2a ↓
ubiquitination
FIH Hydroxylation of Asn803 in C-TAD preventing interaction Inhibition of HIF1a transcriptional activity [26,27]
with co-activators
Hydroxylation of Asn851 in C-TAD preventing interaction Inhibition of HIF2a transcriptional activity
with co-activators
HAF Ubiquitination HIF1a ↓ [30,31]
Stabilization Increased HIF2a transcriptional activity
Hsp70/CHIP Binding of Hsp70 leading to CHIP recruitment followed HIF1a ↓ [32]
by ubiquitination
Hsp90 Binding to PAS domain Protection of HIF1a to proteasomal degradation [33]
RACK1 Binding to PAS domain leading to recruitment of elongin- HIF1a ↓ [33]
C and elongin-B followed by ubiquitination
ARD1 Acetylation of Lys532 in ODDD favoring interaction with HIF1a ↓ [34]
pVHL
Destabilization of the a-subunit [35]
p300 Acetylation of Lys709 leading HIF1a protein stability ↑ [36]
GSK3 Phosphorylation of Ser residues in ODDD and N-TAD HIF1a ↓ [37–39]
leading to recruitment of SCF complex and
ubiquitination
p38 Phosphorylation of ID Stabilization of HIF1a [40]
ERK1, ERK2 Phosphorylation of Ser641 and Ser643 HIF1a nuclear translocation and transcriptional [41,42]
activity ↑
ERK1 Phosphorylation of p300 HIF1a transactivation capacity ↑ [43,44]
NO S-nitrosylation of Cys800 leading to increased interaction HIF1a transcriptional activity ↑ [45]
between HIF1a and p300
S-nitrosylation of Cys800 leading to decreased p300 HIF1a transcriptional activity ↓ [46]
binding
SUMO SUMOylation HIF1a stability and transcriptional activity ↑ [47]
SUMOylation leading to enhanced pVHL ubiquitination HIF1a ↓ [48]
of S641 and S643 of HIF1a by ERK1 (also known as SUMOylation can increase the stability and transcrip-
mitogen-activated protein kinase 3, MAPK3) and tional activity of HIF1a. On the other hand, Berta
ERK2 (MAPK1), downstream kinases of the MAPK et al. [48] report that SUMOylation decreased the
pathway, favors nuclear translocation and transcrip- transcriptional activity of HIF1a and enhanced pVHL
tional activity [41,42]. ERK1 is also able to phospho- ubiquitination. It appears that the effect of S-nitrosyla-
rylate p300, which increases the interaction between C- tion and SUMOylation on the HIF1a protein may
TAD and p300 and thereby increasing the transactiva- vary from cell type to cell type.
tion capacity of HIF1a proteins [43,44]. An overview of the post-translational modifications
Another important post-translational modification is regulating the protein levels and activity of the a-sub-
S-nitrosylation. Under normoxic conditions, NO is units can be found in Table 1.
able to stabilize and transactivate HIF1a. Sumbayev
et al. [45] described that HIF1a transcriptional activity
(Post)transcriptional regulation of HIF mRNA
can be stimulated by activating the interaction between
levels
HIF1a and p300 due to S-nitrosylation of the cysteine
800 residue (C800). However, Cho et al. [46] showed Next to the regulation of HIF protein levels via post-
that S-nitrosylation of C800 leads to decreased p300 translational modifications, noncoding RNA and
binding. RNA binding proteins (RBPs) are responsible for the
The final post-translational modification is regulation of the translation via interaction with the 50
SUMOylation. Conflicting results are obtained about and 30 untranslated regions (UTRs) of HIF mRNAs
SUMOylation of HIF1a. Bae et al. [47] suggest that [49]. The expression of HIFa mRNA and proteins can
be regulated by the expression of microRNAs (miRs), to the IREs leading to decreased HIF2a translation
also called hypoxamiRs when induced under hypoxic and protein levels [67].
conditions. miRs downregulate the expression of speci- In summary, three oxygen-sensitive a-subunits are
fic target mRNAs by decreasing the expression of the known, namely HIF1a, HIF2a, and HIF3a. In the
transcript levels or by repressing translation [50]. Dur- presence of oxygen, these HIFa proteins are constantly
ing early hypoxia, miRs will induce the accumulation produced and post-translationally modified by PHD1,
of HIF1a, while maintaining HIF2a and HIF3a at PHD2, or PHD3 leading to ubiquitination of the
steady-state levels. However, during prolonged hypox- HIFa proteins and degradation by the 26S protea-
ia, miRs will increase HIF2a and HIF3a while main- some. Another mechanism that can be used for the
taining HIF1a at low levels. The expression of miR- regulation of HIFa in normoxia is the hydroxylation
210 is upregulated under hypoxic conditions by HIF1a of the C-TAD by FIH. In hypoxia or in the absence
and HIF2a, influencing the expression of HIF target of Fe2+, a-KG or vitamin C, PHDs are inactivated
genes [51,52]. Two other hypoxamiRs are induced by leading to stabilization of the a-subunits. They will
hypoxia, namely miR-155 and miR-429. HIF1a dimerize with the constitutively expressed HIF1b sub-
increases the expression of miR-155 and miR-429 unit and translate to the nucleus inducing transcription
under hypoxic conditions. During prolonged hypoxia, of their target genes. HAF, the Hsp70/CHIP complex,
these miRs will bind to the 3’ UTR of HIF1a, leading and Hsp90 and RACK1 can also regulate the HIFa
to decreased levels of HIF1a mRNA levels and activ- protein levels. Next to ubiquitination and hydroxyla-
ity [53,54]. Besides hypoxamiRs, also two antisense tion, HIFa can also be modulated post-translationally
HIF1A RNA molecules (HIF1A-AS1 and HIF1A- by phosphorylation, acetylation, S-nitrosylation, and
AS2) have been identified. The expression of these SUMOylation. On the mRNA level, HIFa can be reg-
molecules is upregulated after hypoxia, and they are ulated by hypoxamiRs and RBPs by binding to the 50
able to bind to the 3’ UTR of HIF1a. This leads to or 30 UTR of HIF mRNAs. Finally, HIF itself can
the decay of the HIF1a mRNA [55,56]. bind HREs present in the human HIF1a-coding gene
Hypoxia-inducible factor itself is able to bind HREs HIF1A promotor creating an autoregulatory loop in
present in the human HIF1a-coding gene HIF1A pro- which HIF can upregulate the synthesis of HIF1A
motor creating an autoregulatory loop in which HIF mRNA.
can upregulate the synthesis of HIF1A mRNA [57].
Under hypoxic conditions, the expression of NFjB
Crosstalk between HIF and sepsis
and early growth response protein 1 (Egr1) are upreg-
ulated. Binding sites for these transcription factors are
Inflammation induces hypoxic response
present in the promotor of HIF1A, which leads to
increased transcription of the HIF1A mRNA [58,59]. Hypoxia and inflammation are unequivocally linked.
To have a complete view on the experimentally found Mountain sickness, in essence a phenomenon of sys-
binding sites of transcription factors on the promotors temic hypoxia, results in increased levels of circulating
of all HIFa and HIFb coding human genes, we refer inflammatory cytokines and vascular leakage [68,69].
to the GeneCard tool (www.Genecards.org). Ischemia in organ grafts is directly linked with inflam-
A final manner in which HIF mRNA levels and mation and transplant rejection [26]. Just as hypoxia
translation can be regulated is by binding of RBPs to induces inflammation, inflamed tissue can become
the 50 and/or 30 UTR of HIF transcripts [49]. RBPs hypoxic. Systemic spreading of pathogens during sepsis
like Y-box binding protein 1 (YB-1) [60], Hu antigen is countered by an immediate host response, character-
R (HuR) [61], polypyrimidine tract binding protein ized by intravascular coagulation and the recruitment
(PTB) [62], and cold-inducible RBP (CIRBP) [63] are of immune cells to the site of infection. A downside of
able to increase the stability of the HIF1a mRNA fol- this defense strategy is decreased tissue perfusion and
lowed by elevated protein synthesis. On the other edema resulting in decreased oxygen delivery to cells
hand, tristetraprolin (TTP) RBP family [64], RNA [70]. Furthermore, the influx of the immune cells in
binding motif protein 38 (RBM38) [65], and cytoplas- the inflamed tissues [71] and bacterial replication of
mic polyadenylation element binding proteins 1 and 2 intracellular bacteria can lead to increased oxygen con-
(CPEB1 and CPEB2) [66] bind to the 30 UTR of the sumption and cellular hypoxia [72]. Both decreased
HIF1A mRNA leading to decreased translation. In the oxygen delivery and increased oxygen demand ulti-
50 UTR of the HIF2A mRNA, iron-responsive ele- mately lead to tissue hypoxia during inflammation.
ments (IREs) are present. Low iron concentrations Some cells, such as neurons and cardiomyocytes, rely
induce the binding of iron regulatory proteins (IRPs) primarily on oxidative metabolism and are therefore
very susceptible for hypoxia. Other cell types, such as [80]showed that LPS leads to HIF1a stabilization and
immune cells, can switch to glycolysis under hypoxic activation via increased succinate production. Succi-
conditions and are thus tolerant for hypoxia [73]. The nate can be transported from mitochondria to the
primary signaling pathway activated by hypoxia is the cytosol, where it inhibits PHD via product inhibition
stabilization of the HIFa/HIFb transcription factor [84]. Just as succinate stabilizes HIF, also other
complex. metabolites, such as fumarate, pyruvate, and lactate,
Hypoxia triggers a paradoxical increase in reactive can inhibit PHD resulting in HIF stabilization [85].
oxygen species (ROS) production in the mitochondria. The upregulation of glycolysis by HIF1a and subse-
Low oxygen concentration reduces the mitochondrial quent activation of HIF1a by glycolytic enzymes and
efficiency to generate ATP, leading to proton leakage TCA intermediates creates a positive feedback loop
and ROS production [74]. This leads to ROS-induced that drives macrophages to produce IL1b and ROS
PHD inhibition resulting in increased HIF1a stability resulting in eradication of the invading pathogens [86].
and activity [75]. Possible mechanisms for this ROS-in- Next to the post-translational regulation of HIF,
duced PHD inhibition include oxidation of a-KG to HIF can also be regulated at transcriptional level.
succinate or ferrous iron (Fe2+) to its ferric form Under normoxic conditions, LPS can promote tran-
(Fe3+), thereby depleting PHD from its essential cofac- scription of the HIF1a gene in monocytes and macro-
tors [76]. HIF1a in turn mediates the formation of phages in an NFjB dependent manner [87].
alternative cytochrome c oxidase subunits improving In sepsis, it is believed that both aerobic and anaer-
the efficiency of electron transfer and in this way obic glycolysis appear. After resuscitation, levels of tis-
reduces ROS production under hypoxic conditions sue oxygen tension are preserved or even elevated in
[77]. HIF drives an adaptive response to hypoxia via failed organs providing enough oxygen to meet the
induction of enhanced oxygen delivery and/or increased cellular demands [88]. Indeed, lactate pro-
decreased oxygen demand. By promoting the expres- duction may increase even without any oxygen delivery
sion of genes that regulate erythropoiesis (EPO) and compromise [89,90] (Figure 3). For example, the con-
angiogenesis (VEGF), HIF increases oxygen delivery to version of pyruvate to lactate requires NADH and H+.
hypoxic tissues. These processes are important in Conditions that increase the NADH/NAD+ ratio, such
chronic hypoxic conditions, such as cancer and inflam- as ketoacidosis or mitochondrial dysfunction, can thus
matory bowel disease (IBD). promote lactate production independently of tissue
Short-term adaptations to hypoxia are more impor- oxygenation [90]. Next, in sepsis mitochondrial dys-
tant in acute hypoxic conditions such as inflammation. function has been reported and this in turn shifts
This includes a switch from mitochondrial respiration metabolism toward glycolysis, even in the presence of
to anaerobic glycolysis and thus reduced oxygen oxygen. This is the so-called Warburg effect. Hypoxia
demand and increased glucose consumption [78]. Gly- can lead to mitochondrial shutdown to limit oxygen
colytic genes induced by HIF1a include hexokinase consumption as these organelles are highly oxygen
(HK1), phosphofructokinase-1 (PFK1), glucose-6-phos- consuming necessary for ATP and heat production.
phate dehydrogenase (G6PD), lactate dehydrogenase Oxygen-independent mechanisms of mitochondrial
(LDH), pyruvate dehydrogenase kinase (PDK1), and shutdown include (a) damage to mitochondrial pro-
glutamate transporter-1 (SLC1A3) [79]. In addition to teins induced by excess amounts of NO, carbon
metabolic regulation, HIF1a also directly contributes monoxide and hydrogen sulfide, (b) hormonal alter-
to the production of pro-inflammatory cytokines such ations such as thyroid increase affects mitochondrial
as IL1b [80] and regulates the expression of NOS2 efficiency, and (c) decreased transcription of mitochon-
mRNA [81] and phagosomal proteases, promoting drial proteins due to inflammation [78].
bactericidal killing [82].
Interestingly, HIF can also be activated under nor-
The role of HIF in sepsis patients
moxic conditions, thus before tissues become hypoxic.
Bacteria can increase HIF1a protein expression and Recently, a clinical trial investigating HIF as a novel
stimulate HIF1a transcriptional activity more than biomarker for septic shock has been completed
hypoxia itself [82]. A way of doing this is via limiting (NCT02163473), but results remain to be published.
iron availability, an essential prerequisite for PHD Several studies have found a link between HIF and
enzymatic activity, by the bacterial siderophores [83]. sepsis. A recent genome-wide array study with severe
Also, host-derived ferritin induced by inflammation community-acquired pneumonia proposed two differ-
can sequester iron and in this way activate HIF inde- ent gene expression patterns in leukocytes of sub-
pendently of oxygen availability [84]. Tannahill groups of patients, termed sepsis response states SRS1
and SRS2 [91]. The SRS1 group was related to higher years, there was somehow a rediscovery of metabolism
mortality and features of immunosuppression. The by immunologists and the term immunometabolism
authors identified regulatory genetic variants account- emerged [79]. It has become clear that metabolic repro-
ing for an upregulated expression of HIF1a, HIF2a en gramming in activated immune cells is not only impor-
LDHa in SRS1. This implies that genetic variations tant for their increased energetic demands but can also
associated with the expression of genes could provide be directly linked to the immune cell functions. Just as
information about the immune response state and in inflammation, cellular metabolism is at the cross-
prognosis of the patient. This study creates opportuni- roads of other disciplines, such as aging and cancer.
ties for the development of new interventions, identifi- Here, we will discuss briefly metabolic changes that
cation of high-risk patients, and ultimately individually occur in innate and adaptive immunity during sepsis.
targeted therapy [91]. Another study also identified sig-
nificantly higher HIF1a mRNA expression in whole-
Innate immunity
blood samples derived from septic shock patients.
However, this could not be correlated with the out- The innate immune response is the first line of host
come of patients. A limitation of this study was the defense found in all multicellular organisms. The
small group of patients [92]. Shalova et al. [93] innate immune system has evolved to protect the host
reported an increased expression of HIF1a in sepsis from the surrounding environment in which a variety
derived monocytes, but not in monocytes derived from of infectious agents such as bacteria, fungi, viruses,
recovered patients. In contrast, Schafer et al. [94] and parasites are found. It consists of physical barriers
showed a decrease of HIF1a mRNA and protein and effector cells such as macrophages, dendritic cells
expression in leukocytes of sepsis patients and this was (DCs), and neutrophils. This natural immune response
inversely associated with the severity of sepsis. is designed to (a) prevent infection, (b) eliminate inva-
der pathogens, and (c) stimulate the adaptive immune
response. For an extensive review on the role of
Role of HIF in immunometabolism
HIF1a in myeloid cells, we refer to the recent review
Activation of immune cells during inflammation is of Stothers et al. [86]. Here, we will discuss briefly the
associated with rapid and fundamental changes in their role of HIF1a in monocyte, neutrophil, and DC func-
metabolism. Switching from oxidative phosphorylation tion.
to glycolysis provides the necessary energy and build- HIF1a is found to be a regulator of monocyte func-
ing blocks swiftly to meet their rapid division and bio- tional reprogramming during sepsis. Blood monocytes
energetic demands during inflammation. In recent from septic patients show a transition from a pro-in-
flammatory state to an immunosuppressive state, and
HIF1a is found to be the key modulator herein. Blood
monocytes derived from septic patients have a higher
HIF1a expression and activity as compared to recov-
ery-monocytes. HIF1a in turn induces IRAKM, a neg-
ative regulator of the TLR signaling pathway and
inducer of endotoxin tolerance, thereby driving these
cells into an endotoxin-tolerant state [93]. In contrast
to reducing inflammation, HIF1a is well known to
enhance inflammation by stimulating pro-inflamma-
tory cytokine production including IL1b, TNF, IL6,
IL4, and IL12 expression. Conditional knockout of
HIF1a in macrophages protects against LPS-induced
mortality via reducing inflammatory cytokine produc-
tion [80,95] and counteracting LPS-induced hypo-
Fig. 3. Dual role of HIF in sepsis. During sepsis, several factors glycemia [96]. Furthermore, macrophages isolated
can induce HIF activation. The consequences of HIF activation in from PHD2 and HIF1a double-knockout mice show
sepsis are twofold. On the one hand, HIF activation in immune
an increased oxygen consumption and a decline in lac-
cells during sepsis is pivotal as this is important to combat the
infection. On the other hand, the increased glycolysis as a result of
tate concentration [95]. Next to HIF1a, HIF2a also
HIF activation leads to an accumulation of lactate and thereby also contributes to sepsis pathology. Absence of HIF2a in
a decrease in pH. Increased blood lactate levels are found to be myeloid cells also protected against LPS-induced sepsis
negatively associated with patient outcome. by a disrupted balance between pro- and anti-
inflammatory cytokine production resulting in an hypoxia experienced in germinal centers has a role in
immunosuppressive milieu [97]. Absence of PHD3 in determining the B-cell phenotype. Indeed, B-cell
myeloid cells leads to an enhanced pro-inflammatory hypoxia in germinal centers leads to a decreased prolif-
response due to increased HIF1a protein stabilization eration and altered immunoglobulin class switching of
and increased NFjB activity [98]. B cells [109,110]. The use of HIF1a-deficient chimeric
Whether HIF1a dampens or enhances inflammation mice confirms the important role for HIF1a in the
could potentially be an effect of timing. Initial HIF1a development of B cells and autoimmunity [111], and
activation induces a pro-inflammatory state, whereas recently, a critical role for HIF1a in B cells for IL-10
chronic activation of this pathway during sepsis would production has been identified [112].
lead to dampening of the inflammatory response [99].
In neutrophils, HIF1a promotes survival and bacterici-
HIF as a therapeutic target for sepsis
dal activity. HIF1a deletion in neutrophils is accompa-
nied by reduced production of granule proteases, Based on the current ideas of HIF in sepsis, it would
CRAMP and NO [93], and makes mice more suscepti- be of great interest to use HIF as a potential new ther-
ble for S. aureus infection [100]. NO in turn recipro- apeutic target in sepsis. Several preclinical studies have
cally regulates the stability of HIF1a. HIF1a has also been reported where HIF has been targeted directly or
been shown to promote cell survival, interferon synthe- indirectly.
sis, differentiation, and migration in DCs [101].
Recently, it was found that echinomycin, an inhibitor
Targeting HIF in an indirect way
of HIF1 DNA binding and transcriptional activity,
prevents the secretion of pro-inflammatory cytokines The PHD inhibitor dimethyloxallyl glycine (DMOG)
by DCs [102–104]. is able to protect against LPS-induced endotoxemia by
attenuating the NFjB pathway. Conversely, mice trea-
ted with DMOG could not be protected against
Adaptive immunity
polymicrobial sepsis, due to suppressing the inflamma-
The adaptive immune system is the second line of host tory response followed by an overwhelming infection
defense and only found in vertebrates. The adaptive [113]. Pretreatment of mice with another PHD inhibi-
response is specific for the pathogen encountered. Basi- tor, 3,4-dihydroxybenzoate (3,4-DHB), improves renal
cally, it consists of clonal expansion of T- and B-lym- function after cecal ligation and puncture (CLP); how-
phocytes. ever, the PHD inhibition leads to an increased mortal-
HIF1a has been reported to regulate T-cell survival, ity rate due to liver dysfunction with massive glycogen
proliferation, and differentiation. Indeed, HIF1a acti- loss and apoptosis of hepatocytes [114]. Treatment
vation promotes a metabolic shift toward glycolysis with Edaravone, a potent radical scavenger, suppresses
needed for the differentiation of na€ıve T cells toward oxidative stress and protects against septic myocardial
Th1, Th2, and Th17 cells [105]. In activated T cells, injury and dysfunction by HIF1a activation and subse-
HIF1a has been reported to promote cytolytic, migra- quent heme oxygenase 1 induction [115]. 5,7-dihy-
tory, and costimulatory properties. Furthermore, droxy-8-methoxyflavone (DHMF) is able to protect
HIF1a activation in regulatory T cells (Tregs) via against LPS-induced acute lung injury by upregulating
pVHL depletion leads to massive IFNc production, antioxidant enzymes. Also, pretreatment with DHMF
leading to the induction of a Th1-like phenotype. inhibits phosphorylation of NFjB and leads to an
Silencing of HIF1a in Tregs restores their suppressive accumulation of HIF1a by increasing the hydroxyla-
function [106]. HIF1a plays also a role in Th17/Treg tion of Pro residues by PHDs and pVHL [116]. This is
balance via induction of RORct and targeting Foxp3 in contrast with the previous study, where HIF1a acti-
for degradation [107]. In contrast to the above-men- vation is increased [115]. Treatment with the statin
tioned studies, Clambey et al. [108] showed that Foxp3 Simvastatin protects mice against lethal LPS injection
is a direct target gene for HIF1a promoting the func- by decreasing the hepatocellular degeneration in early
tion of Tregs. Loss of HIF1a in Tregs resulted in phases of sepsis by reducing HIF1a levels [117].
reduced anti-inflammatory capacity and loss of con- The impact of HIF and hypoxia on the function of
trolling inflammation. These apparent opposing results immune cells identifies new potential therapeutic tar-
indicate that HIF1a can direct multiple T-cell fates. gets for inflammatory diseases. Currently, four PHD
Probably, the ultimate fate of T cells in hypoxia is inhibitors are known to be in clinical use or in a clini-
dependent on the specific cytokine environment. In B cal trial for the treatment of anemia, a commonly
cells, it has recently been shown that the physiological known complication in chronic kidney disease, namely
Roxadustat [118,119], Vadadustat [120,121], Dapro- More research is required to determine the mecha-
dustat [122], and Molidustat [123]. The development nisms by which liberal oxygen therapy harms acutely
of inhibitors for specific PHD isoforms or FIH and ill patients. Although liberal oxygen therapy increased
selective HIF1 versus HIF2 inhibitors would be of the mortality rate, it has been proposed that liberal
great interest and would improve the therapeutic oxygen therapy during surgery and the immediate
potential of interfering with the HIF pathway. postoperative period reduces the risk of surgical-site
infections (infections that occur after surgery in the
part of the body where the surgery took place) [133].
Direct targeting of HIF
It would be of great interest to find a balance between
An endogenous metabolite from estradiol, 2- the benefits of oxygen therapy on surgical-site infec-
methoxyestradiol (2-ME), prolongs survival against tions and the harms of increased mortality. The Oxy-
LPS- and CLP-induced sepsis. Pharmacological gen-ICU randomized control clinical trial showed that
downregulation of HIF1a and its transcriptional conservative oxygen therapy in critically ill patients
activity by 2-ME induces a decreased cytokine and might have a potential beneficial effect. However, a
NO production in peritoneal macrophages, suggest- larger multicenter trial will be necessary to further
ing an important role of HIF1a expression in mye- evaluate the positive effects of conservative oxygena-
loid cells in sepsis survival [124,125]. The HIF1a tion [134,135]. Precise control of the arterial oxygena-
agonist L-mimosine is able to enhance the bacterici- tion and the identification of biomarkers for the
dal capacities of human phagocytes due to the stabi- susceptibility to hypoxia or hyperoxia would improve
lization of HIF1a. Treatment with L-mimosine leads further follow-up of individual patients during oxygen
to enhanced killing of an S. aureus infection in vitro therapy and could be used for the modification of
and in vivo [126]. HIF2a-specific inhibitors have been therapeutic strategies [131,132].
developed and show efficacy against renal cancers
[127,128]. However, the effect of these HIF2a inhibi-
The role of HIF in other inflammatory diseases
tors in immunity and inflammation is currently
unknown. Inflammatory bowel disease
Inflammatory bowel disease is a chronic intestinal
Oxygen therapy in sepsis patients inflammatory disorder resulting from a dysregulated
host response in genetically predisposed people. It
Oxygen therapy is frequently administered to acutely
compromises Crohn’s disease (CD) and ulcerative coli-
ill patients. Oxygen supplementation is considered by
tis (UC). In basal conditions, the intestinal epithelium
many healthcare providers as a harmless and poten-
is already in a state of physiological hypoxia due to
tially beneficial therapy, irrespective of the presence of
changes in blood flow and tissue oxygenation. This
hypoxia (lack of oxygen at tissue level) and hypoxemia
hypoxic state is potentiated in IBD by increased oxy-
(low blood oxygen levels). In recent years, clinical tri-
gen demand and decreased blood supply [136]. It is
als have been investigating the effect of liberal oxygen
shown that HIF1a has an important role in UC. In
therapy using 100% oxygen (hyperoxia, leading to
mice, the deletion of HIF1a in the intestinal epithelial
oxygen saturation levels (SpO2) in the blood > 97%)
cells (IECs) leads to increased susceptibility to intesti-
compared to conservative oxygen therapy (80% oxy-
nal inflammation [137], whereas stabilization of HIF1a
gen, SpO2 between 94% and 97%). The HYPERS2S
by PHD inhibitors has a protective effect, for example,
trial (NCT01722422) showed that hyperoxia treatment
DMOG [138], AKB-4924 [139]. Loss of HIF2a in the
for 24 h in septic shock patients with a mean arterial
IECs protects mice against acute colitis, in contrast to
pressure > 65 mmHg and lactate levels > 2 mM despite
HIF1a [140].
adequate fluid resuscitation is associated with a higher
mortality rate [129,130]. In agreement with this study,
Chu et al. [131] observed a dose-dependent increased Ischemia–reperfusion
risk in short-term and long-term mortality when
An inadequate blood supply to an organ or other part
patients were treated liberally with oxygen. The
of the body is defined as ischemia, for example,
increased mortalities observed with excessive oxygen
myocardial ischemia and liver ischemia. This is charac-
treatment is a result of increased inflammation, oxida-
terized by a reduced nutrient and oxygen supply as
tive stress on cardiovascular, pulmonary and neurolog-
well as a reduced elimination of waste products of the
ical systems, and vasoconstriction in the patient
tissue, causing irreversible tissue damage and death
[131,132].
[141]. Upon reperfusion, the tissue is provided again HIF pathway can be used as a therapeutic target
with nutrients and oxygen. However, this can cause during transplantation [151]. Several studies indicate
serious tissue damage by the release of ROS, DNA, that HIF activators protect against acute graft fail-
and lipids. Ischemia inhibits PHDs leading to stabiliza- ure during transplantation. PHD1-deficient mice are
tion of HIF and HIF-induced gene expression. Due to protected against ischemia–reperfusion injury in the
the release of ROS, HIF remains stabilized upon liver due to increased levels of HIF2a, and to lesser
reperfusion, inducing a prolonged hypoxic phenotype extent HIF1a [152]. Also, the use of DMOG as a
[142]. Ischemic preconditioning, acute cycles of ische- preconditioning agent to renal ischemia–reperfusion
mia followed by reperfusion, reduces the infarct size injury could be very useful in kidney transplantation
resulting in a protecting phenotype in which HIF1a [153].
stabilization and transactivation is important. HIF1a+/

mice are less protected by preconditioning in a heart
Conclusion
ischemia–reperfusion model [143]. Also, pretreatment
with DMOG induces cardioprotection to the same The studies described above highlight the interdepen-
extent as preconditioning [144]. Furthermore in a renal dent relationship between inflammation and hypoxia.
ischemic model, stabilization of HIF1a and HIF2a by HIF regulation is dependent on the oxygen availabil-
PHD inhibition (FG-4487) induces a protective effect ity, but also on redox status, nutrient availability
[145]. and certain inflammatory markers can stabilize HIF.
The HIF pathway is critically involved in regulating
adaptations to low oxygen levels and has also a crit-
Infectious diseases
ical role in immunometabolism. It has become clear
Upon infection, a hypoxic microenvironment is cre- that HIF promotes the immune functions in both
ated which is important for the function of tissue innate and adaptive immunity resulting in increased
macrophages and infiltrating neutrophils [146]. Stabi- bactericidal activities. Targeting hypoxia in infection
lization of HIF1a, by low oxygen levels or reduced and inflammation can thus form the basis of novel
PHD activity due to iron uptake by bacteria, is therapeutic strategies. Interestingly, the observation
essential for the bacterial uptake, production of that succinate can stabilize HIF in macrophages
antimicrobial molecules, and longevity of neutrophils. illustrates a role for metabolites outside their cognate
Also, the glucose metabolism of phagocytes is sup- functions. Further understanding of metabolic
ported by HIF1a [69]. The absence of HIF1a in changes that underlie HIF activation poses
myeloid cells leads to decreased bactericidal activity alternative therapeutic strategies to modulate immune
of phagocytes. On the contrary, loss of VHL in function via the manipulation of metabolic
myeloid cells induces an enhanced acute inflamma- pathways.
tory response [95,147]. The PHD inhibitor AKB- Interfering with HIF signaling should however be
4924 mainly stabilizes HIF1a and shows the antimi- done with great care. First, HIF has pleiotropic func-
crobial activity since it enhances the killing of Pseu- tions (erythropoiesis, angiogenesis), and in order to
domonas aeruginosa (Ps. aeruginosa) and reduce possible side effects, developing more tissue-
Acinetobacter baumannii [148,149]. Also, the use of specific delivery systems warrants further research.
DMOG inducing stabilization of HIF2a significantly Furthermore, the role of HIF is extensively studied in
attenuates pulmonary infections with Ps. aeruginosa immune cells, but its function and the adaptive
[150]. These studies show that both HIF1a and responses to hypoxia in parenchyma tissue are still
HIF2a can be important in the killing of bacterial unknown. Second, inhibition of inflammation limits
infections. exaggerated immune responses during sepsis, but
undermines the essential functions of immune cells,
namely proper clearage of infection. It is thus of
Organ transplantation
utmost importance to find a balance between up (an-
Solid-organ transplantation, for example, liver, heart timicrobial)- and down (anti-inflammatory)-regulating
and lung, is frequently followed by early graft fail- immune cell functions. Third, HIF has been shown to
ure. This is caused by ischemia–reperfusion injury be involved in both hyperinflammatory and immuno-
and is associated with high morbidity and mortality tolerant phases of sepsis. Further studies are warranted
rates. Nowadays, there is a growing list of patients to study the time-dependent effects of HIF during the
with an urgent need for transplantation and a scar- different phases of inflammation. Finally, the role of
city of grafts available for transplantation, and the HIF1a is quite extensively studied in sepsis; however,
the role of other HIF isoforms during sepsis could also 7 Lee J-W, Bae S-H, Jeong J-W, Kim S-H & Kim K-W
be of great interest. (2004) Hypoxia-inducible factor (HIF-1)alpha: its
protein stability and biological functions. Exp Mol
Med 36, 1–12.
Acknowledgements 8 Wang GL & Semenza GL (1995) Purification and
Research in the author’s laboratory was funded by characterization of hypoxia-inducible factor 1. J Biol
The Agency for Innovation of Science and Technology Chem 270, 1230–1237.
in Flanders (IWT), The Research Council of Ghent 9 Loboda A, Jozkowicz A & Dulak J (2010) HIF-1 and
HIF-2 transcription factors–similar but not identical.
University (GOA Program), The Research Foundation
Mol Cells 29, 435–442.
Flanders (FWO Vlaanderen), COST Action BM1402,
10 Kasper LH, Boussouar F, Boyd K, Xu W, Biesen M,
and The Interuniversity Attraction Poles Program of
Rehg J, Baudino TA, Cleveland JL & Brindle PK
the Belgian Science Policy (IAP-VI-18). TV is funded
(2005) Two transactivation mechanisms cooperate for
by the Research Council of Ghent University (GOA
the bulk of HIF-1-responsive gene expression. EMBO
Program), and JV is a research fellow with the J 24, 3846–3858.
Research Foundation Flanders (FWO Vlaanderen). 11 Loboda A, Jozkowicz A & Dulak J (2012) HIF-1
versus HIF-2 - Is one more important than the other?
Conflict of interest Vascul Pharmacol 56, 245–251.
12 Hu C, Sataur A, Wang L, Chen H & Simon MC
The authors declare no conflict of interest. (2007) The N-terminal transactivation domain confers
target gene specificity of hypoxia-inducible factors
HIF-1a and HIF-2a. Mol Biol Cell 18, 4528–4542.
Author contributions
13 Gu Y, Moran SM, Hogenesch JB, Wartman L &
TV and JV contributed equally to this work. CL Bradfield CA (1998) Molecular characterization and
supervised the manuscript. chromosomal localization o f a third a-class hypoxia
inducible factor subunit, HIF3a. Gene Expr 7, 205–
213.
References 14 Hara S, Hamada J, Kobayashi C, Kondo Y & Imura
1 Rudd KE, Kissoon N, Di L, Bory S, Mutahunga B, N (2001) Expression and characterization of hypoxia-
Seymour CW, Angus DC & West TE (2018) The inducible factor (HIF)-3a in human kidney :
global burden of sepsis: barriers and potential suppression of HIF-mediated gene expression by HIF-
solutions. Crit Care 22, 232. 3a. Biochem Biophys Res Commun 287, 808–813.
2 Singer M, Deutschman CS, Seymour C, Shankar-Har 15 Makino Y, Uenishi R, Okamoto K, Isoe T, Hosono
M, Annane D & Angus DC (2016) The Third O, Tanaka H, Kanopka A, Peollinger L, Haneda M &
International Consensus Definitions for Sepsis and Morimoto C (2007) Transcriptional up-regulation of
Septic Shock (Sepsis-3). JAMA 315, 801–810. inhibitory PAS domain protein gene expression by
3 Singer M, Deutschman CS, Seymour C, Manu S-H, hypoxia-inducible factor 1 (HIF-1) a negative feedback
Annane D, Bauer M, Bellomo R, Bernard GR, Chiche regulatory circuit in HIF-1-mediated signaling in
J-D, Coopersmith CM et al. (2016) The Third hypoxic cells. J Biol Chem 282, 14073–14082.
International Consensus Definitions for Sepsis and 16 Iyer NV, Kotch LE, Agani F, Leung SW, Laughner E,
Septic Shock {(Sepsis-3)}. JAMA 315, 801–810. Wenger RH, Gassmann M, Gearhart JD, Lawler AM,
4 Langley RJ, Tsalik EL, van Velkinburgh JC, Glickman Yu AY et al. (1998) Cellular and developmental
SW, Rice BJ, Wang C, Chen B, Carin L, Suarez A, control of O2 homeostasis by hypoxia-inducible factor
Mohney RP et al. (2013) An integrated clinico- 1a. Genes Dev 12, 149–162.
metabolomic model improves prediction of death in 17 Peng J, Zhang L, Drysdale L & Fong G (2000) The
sepsis. Sci Transl Med 5, 1–33. transcription factor EPAS-1/hypoxia-inducible factor
5 Van Wyngene L, Vandewalle J & Libert C (2018) 2a plays an important role in vascular remodeling.
Reprogramming of basic metabolic pathways in Proc Natl Acad Sci USA 97, 8386–8391.
microbial sepsis: therapeutic targets at last? EMBO 18 Yamashita T, Ohneda O, Nagano M, Iemitsu M,
Mol Med 10, e8712. Makino Y, Tanaka H, Miyauchi T, Goto K, Ohneda
6 Iwashyna TJ, Ely EW, Smith DM & Langa KM K, Fujii-kuriyama Y et al. (2008) Abnormal heart
(2010) Long-term cognitive impairment and functional development and lung remodeling in mice lacking the
disability among survivors of severe sepsis. JAMA 304, hypoxia-inducible factor-related basic helix-loop-helix
1787–1794. PAS Protein NEPAS. Mol Cell Biol 28, 1285–1297.
19 Kaelin WG & Ratcliffe PJ (2008) Oxygen sensing by characteristics, aggressive tumor growth and invasion.
metazoans: the central role of the HIF hydroxylase Cancer Res 71, 4015–4027.
pathway. Mol Cell 30, 393-402. 32 Luo W, Zhong J, Chang R, Hu H, Pandey A &
20 Salceda S & Caro J (1997) Hypoxia-inducible factor Semenza GL (2010) Hsp70 and CHIP selectively
1alpha (HIF-1alpha) protein is rapidly degraded by the mediate ubiquitination and degradation of hypoxia-
ubiquitin-proteasome system under normoxic inducible factor (HIF)-1a but not HIF-2a. J Biol Chem
conditions. Its stabilization by hypoxia depends on 285, 3651–3663.
redox-induced changes. J Biol Chem 272, 22642–22647. 33 Liu YV, Baek JH, Zhang H, Diez R, Cole RN &
21 Berra E, Benizri E, Volmat V, Ginouve A, Roux D & Semenza GL (2007) Article RACK1 competes with
Pouyssegur J (2003) HIF prolyl-hydroxylase 2 is the HSP90 for binding to HIF-1 a and is required for O 2
key oxygen sensor setting low steady-state levels of -independent and HSP90 inhibitor-induced degradation
HIF-1 a in normoxia. EMBO J 22, 4082–4090. of HIF-1 a. Mol Cell 25, 207–217.
22 Appelhoff RJ, Tian Y, Raval RR, Turley H, Harris 34 Jeong J, Bae M, Ahn M, Kim S, Sohn T, Bae M, Yoo
AL, Pugh CW, Ratcliffe PJ & Gleadle JM (2004) M, Song EJ, Lee K & Kim K (2002) Regulation and
Differential function of the prolyl hydroxylases PHD1, destabilization of HIF-1a by ARD1-mediated
PHD2, and PHD3 in the regulation of hypoxia- acetylation. Cell 111, 709–720.
inducible factor. J Biol Chem 279, 38458–38465. 35 Arnesen T, Kong X, Evjenth R, Gromyko D, Varhaug
23 Webb JD, Coleman ML & Pugh CW (2009) Hypoxia, JE, Lin Z, Sang N, Caro J & Lillehaug JR (2005)
hypoxia-inducible factors (HIF), HIF hydroxylases Interaction between HIF1a (ODD) and hARD1 does
and oxygen sensing. Cell Mol Life Sci 1, 3539–3554. not induce acetylation and destabilization of HIF1a.
24 Maxwell PH, Wiesener MS, Chang G-W, Clifford SC, FEBS Lett 579, 6428–6432.
Vaux EC, Cockman ME, Wykoff CC, Pugh CW, 36 Geng H, Liu Q, Xue C, David LL, Beer TM, Thomas
Maher ER & Ratcliffe PJ (1999) The tumour GV, Dai M & Qian DZ (2012) HIF1a protein stability
suppressor protein VHL targets hypoxia-inducible is increased by acetylation at lysine 709. J Biol Chem
factors for oxygen-dependent proteolysis. Nature 399, 287, 35496–35505.
271–275. 37 Fl€ugel D, G€orlach A, Michiels C & Kietzmann T
25 Cockman ME, Masson N, Mole DR, Jaakkola P, (2007) Glycogen synthase kinase 3 phosphorylates
Chang G, Clifford SC, Maher ER, Pugh CW, Ratcliffe hypoxia-inducible factor 1a and mediates its
PJ & Maxwell PH (2000) Hypoxia inducible factor-a destabilization in a VHL-independent manner. Mol
binding and ubiquitylation by the von Hippel-Lindau Cell Biol 27, 3253–3265.
tumor suppressor protein *. J Biol Chem 275, 25733– 38 Fl€ugel D, G€orlach A & Kietzmann T (2012) GSK-3b
25741. regulates cell growth, migration, and angiogenesis via
26 Schofield CJ & Ratcliffe PJ (2004) Oxygen sensing by Fbw7 and USP28-dependent degradation of HIF-1a.
HIF hydroxylases. Nat Rev Mol Cell Biol 5, 343–354. Vasc Biol 119, 1292–1302.
27 Wong BW, Kuchnio A, Bruning U & Carmeliet P 39 Cassavaugh JM, Hale SA, Wellman TL, Howe AK,
(2013) Emerging novel functions of the oxygen-sensing Wong C & Lounsbury KM (2011) Negative regulation
prolyl hydroxylase domain enzymes. Trends Biochem of HIF1a by FBW7-mediated degradation pathway
Sci 38, 3–11. during hypoxia. J Cell Biochem 3890,
28 Semenza GL, Agani F, Booth G, Forsythe J, Iyer N, 3882–3890.
Jiang BH, Leung S, Roe R, Wiener C & Yu A (1997) 40 Sodhi A, Montaner S, Miyazaki H & Gutkind JS
Structural and functional analysis of hypoxia-inducible (2001) MAPK and Akt act cooperatively but
factor 1. Kidney Int 51, 553–555. independently on hypoxia inducible factor-1a in
29 Smythies JA, Sun M, Masson N, Salama R, Simpson rasV12 upregulation of VEGF. Biochem Biophys Res
PD, Murray E, Neumann V, Cockman ME, Choudhry Commun 287, 292–300.
H, Ratcliffe PJ et al. (2019) Inherent DNA – binding 41 Mylonis I, Chachami G, Samiotaki M, Panayotou G,
specificities of the HIF- 1 a and HIF- 2 a transcription Paraskeva E, Kalousi A, Georgatsou E, Bonanou S &
factors in chromatin. EMBO Rep 20, 1–17. Simos G (2006) Identification of MAPK
30 Koh MY, Darnay BG & Powis G (2008) Hypoxia- phosphorylation sites and their role in the localization
associated factor, a novel E3-ubiquitin ligase, binds and activity of hypoxia-inducible factor-1a*. J Biol
and ubiquitinates hypoxia-inducible factor 1a, leading Chem 281, 33095–33106.
to its oxygen-dependent degradation. Mol Cell Biol 28, 42 Triantafyllou A, Liakos P, Tsakalof A, Georgatsou E,
7081–7095. Simos G & Bonanou S (2006) Cobalt induces hypoxia-
31 Koh MY, Lemos R Jr, Liu X & Powis G (2011) The inducible factor-1 a ( HIF-1 a ) in HeLa cells by an
hypoxia-associated factor switches cells from HIF1a- iron-independent, but ROS-, PI-3K- and MAPK-
to HIF2a-dependent signaling promoting stem cell dependent mechanism. Free Radic Res 40, 847–856.
43 Gradin K, Takasaki C, Fujii-Kuriyama Y & Sogawa 56 Rossignol F, de Laplanche E, Mounier R, Bonnefont

K (2002) The transcriptional activation function of the J, Cayre A, Godinot C, Simonnet H & Clottes E
HIF-like factor requires phosphorylation at a (2004) Natural antisense transcripts of HIF-1 a are
conserved threonine *. J Biol Chem 277, 23508–23514. conserved in rodents. Gene 339, 121–130.
44 Sang N, Stiehl DP, Bohensky J, Leshchinsky I, 57 Minet E, Ernest I, Michel G, Roland I, Remacle J,
Srinivas V & Caro J (2003) MAPK signaling up- Raes M & Michiels C (1999) HIF1A gene
regulates the activity of hypoxia-inducible factors by transcription is dependent on a core promoter
its effects on p300*. J Biol Chem 278, 14013–14019. sequence encompassing activating and inhibiting
45 Sumbayev VV, Budde A, Zhou J & Br€ une B (2003) sequences located upstream from the transcription
HIF-1 K protein as a target for S-nitrosation. FEBS initiation site and cis elements located within the 5’
Lett 535, 106–112. UTR. Biochem Biophys Res Commun 261, 534–540.
46 Cho H, Ahn D, Park H & Yang EG (2007) Modulation 58 Belaiba RS, Bonello S, Z€ahringer C, Schmidt S, Hess
of p300 binding by posttranslational modifications of the J, Kietzmann T & G€ orlach A (2007) Transcription by
C-terminal activation domain of hypoxia-inducible involving phosphatidylinositol 3-kinase and nuclear
factor-1 a. FEBS Lett 581, 1542–1548. factor k B in pulmonary artery smooth muscle cells.
47 Bae S, Jeong J, Park JA, Kim S, Bae M, Choi S & Mol Biol Cell 18, 4691–4697.
Kim K (2004) Sumoylation increases HIF-1 stability 59 Sperandio S, Fortin J, Sasik R, Robitaille L, Corbeil J
and its transcriptional activity. Biochem Biophys Res & de Belle I (2009) The transcription factor Egr1
Commun 324, 394–400. regulates the HIF-1 a gene during hypoxia. Mol
48 Berta A, Mazure N, Hattab M, Pouysse J & Brahimi- Carcinog 48, 38–44.
horn MC (2007) SUMOylation of hypoxia-inducible 60 El-Naggar AM, Veinotte CJ, Cheng H, Grunewald
factor-1 a reduces its transcriptional activity. Biochem TGP, Negri GL, Somasekharan SP, Corkery DP,
Biophys Res Commun 360, 646–652. Tirode F, Mathers J, Khan D et al. (2015)
49 Ivanova IG, Park CV & Kenneth NS (2019) Translational activation of HIF1 a by YB-1 promotes
Translating the Hypoxic Response — the Role of HIF sarcoma metastasis. Cancer Cell 27, 682–697.
Protein Translation in the Cellular Response to Low 61 Gauchotte G, Hergalant S, Vigouroux C, Casse J,
Oxygen. Cells 8, 1–15. Houlgatte R, Kaoma T, Helle D, Brochin L, Rech F,
50 Serocki M, Bartoszewska S, Janaszak-Jasiecka A, Pyere M et al. (2017) Cytoplasmic overexpression of
Renata JO, Collawn JF & Bartoszewski R (2018) RNA-binding protein HuR is a marker of poor
miRNAs regulate the HIF switch during hypoxia : a prognosis in meningioma, and HuR knockdown
novel therapeutic target. Angiogenesis 21, 183–202. decreases meningioma cell growth and resistance to
51 Huang Y, Zhao JJ, Lv YY, Ding PS & Liu RY (2009) hypoxia. J Pathol 242, 421–434.
Hypoxia down-regulates glucocorticoid receptor alpha 62 Galban S, Kuwano Y, Pullmann R, Martindale JL,
and attenuates the anti-inflammatory actions of Kim HH, Lal A, Abdelmohsen K, Yang X, Dang Y,
dexamethasone in human alveolar epithelial A549 cells. Liu JO et al. (2008) RNA-binding proteins HuR and
Life Sci 85, 107–112. PTB promote the translation of hypoxia-inducible
52 Chan SY & Loscalzo J (2010) MicroRNA-210: a factor 1a. Mol Cell Biol 28, 93–107.
unique and pleiotropic hypoxamir. Cell Cycle 9, 1072– 63 Lujan DA, Ochoa JL & Hartley RS (2018) Cold-
1083. inducible RNA binding protein in cancer and
53 Bruning U, Cerone L, Neufeld Z, Fitzpatrick SF, inflammation. Wiley Interdiscip Rev RNA 9, 1–18.
Cheong A, Scholz CC, Simpson DA, Leonard MO, 64 Chamboredon S, Ciais D, Desroches-castan A, Savi P,
Tambuwala MM, Cummins EP et al. (2011) Bono F, Feige J-J & Cherradi N (2011) Hypoxia-
MicroRNA-155 promotes resolution of hypoxia- inducible factor-1 a mRNA: a new target for
inducible factor 1a activity during prolonged hypoxia. destabilization by tristetraprolin in endothelial cells.
Mol Cell Biol 31, 4087–4096. Mol Biol Cell 22, 3366–3378.
54 Bartoszewska S, Kochan K, Piotrowski A, Kamysz W, 65 Cho S, Teng I, Zhang M, Yin T, Jung Y, Zhang J &
Ochocka RJ, Collawn JF & Bartoszewski R (2015) Chen X (2014) Hypoxia-inducible factor 1 alpha is
The hypoxia-inducible miR-429 regulates hypoxia- regulated by RBM38, a RNA- binding protein and a
inducible factor-1 a expression in human endothelial p53 family target, via mRNA translation. Oncotarget
cells through a negative feedback loop. FASEB J 29, 6, 305–316.
1467–1479. 66 H€agele S, K€ uhn U, B€ oning M & Katschinski DM
55 Bertozzi D, Iurlaro R, Sordet O, Marinello J, (2009) Cytoplasmic polyadenylation-element-binding
Zaffaroni N & Capranico G (2011) Characterization of protein ( CPEB ) 1 and 2 bind to the HIF-1 a mRNA
novel antisense HIF-1 a transcripts in human cancers. 3 -UTR and modulate HIF-1 a protein expression.
Cell Cycle 10, 3189–3197. Biochem J 417, 235–246.
67 Sanchez M, Galy B, Muckenthaler MU & Hentze MW bactericidal capacity of phagocytes. J Clin Invest 115,
(2007) Iron-regulatory proteins limit hypoxia-inducible 1806–1815.
factor-2 a expression in iron deficiency. Nat Struct Mol 83 Hartmann H, Eltzschig HK, Wurz H, Hantke K,
Biol 14, 420–426. Rakin A, Yazdi AS, Matteoli G, Bohn E, Autenrieth
68 Hackett P & Roach R (2001) High altitude illness. N IB, Karhausen J et al. (2008) Hypoxia-independent
Engl J Med 345, 107–114. activation of HIF-1 by Enterobacteriaceae and their
69 Eltzschig HK & Carmeliet P (2011) Hypoxia and siderophores. Gastroenterology 134, 756–767.e6.
inflammation. N Engl J Med 364, 656–665. 84 Siegert I, Sch€odel J, Nairz M, Schatz V, Dettmer K,
70 Soares MP, Gozzelino R & Weis S (2014) Tissue Dick C, Kalucka J, Franke K, Ehrenschwender M,
damage control in disease tolerance. Trends Immunol Schley G et al. (2015) Ferritin-mediated iron
35, 483–494. sequestration stabilizes hypoxia-inducible factor-1a
71 Cummins EP, Keogh CE, Crean D & Taylor CT upon LPS activation in the presence of ample oxygen.
(2016) The role of HIF in immunity and inflammation. Cell Rep 13, 2048–2055.
Mol Aspects Med 47-48, 24–34. 85 Iommarini L, Porcelli AM, Gasparre G & Kurelac I
72 Kempf VAJ, Lebiedziejewski M, Alitalo K, W€alzlein (2017) Non-canonical mechanisms regulating hypoxia-
JH, Ehehalt U, Fiebig J, Huber S, Sch€ utt B, Sander inducible factor 1 alpha in cancer. Front Oncol 7, 1–9.
CA, M€ uller S et al. (2005) Activation of hypoxia- 86 Stothers CL, Luan L, Fensterheim BA & Bohannon
inducible factor-1 in bacillary angiomatosis: evidence JK (2018) Hypoxia-inducible factor-1a regulation of
for a role of hypoxia-inducible factor-1 in bacterial myeloid cells. J Mol Med 96, 1293–1306.
infections. Circulation 111, 1054–1062. 87 Frede S, Stockmann C, Freitag P & Fandrey J (2006)
73 Medzhitov R, Schneider DS & Soares MP (2012) Bacterial lipopolysaccharide induces HIF-1 activation
Disease tolerance as a defense strategy. Science 335, in human monocytes via p44/42 MAPK and NF-jB.
936–941. Biochem J 396, 517–527.
74 Hamanaka RB & Chandel NS (2009) Mitochondrial 88 Singer M (2017) Critical illness and flat batteries. Crit
reactive oxygen species regulate hypoxic signaling. Care 21, 309.
Curr Opin Cell Biol 21, 894–899. 89 Levy B, Gibot S, Franck P, Cravoisy A & Bollaert P-
75 Arulkumaran N, Deutschman CS, Pinsky MR, E (2005) Relation between muscle Na+K+ ATPase
Zuckerbraun B, Schumacker PT, Gomez H, Gomez A, activity and raised lactate concentrations in septic
Murray P & Kellum JA (2016) Mitochondrial function shock: a prospective study. Lancet 365, 871–875.
in sepsis. Shock 45, 271–281. 90 Suetrong B & Walley KR (2016) Lactic acidosis in
76 Hirsil€a M, Koivunen P, G€ unzler V, Kivirikko KI & sepsis: it’s not all anaerobic: implications for diagnosis
Myllyharju J (2003) Characterization of the human and management. Chest 149, 252–261.
prolyl 4-hydroxylases that modify the hypoxia- 91 Davenport EE, Burnham KL, Radhakrishnan J,
inducible factor. J Biol Chem 278, 30772–30780. Humburg P, Hutton P, Mills TC, Rautanen A,
77 Fukuda R, Zhang H, Kim J-w, Shimoda L, Dang CV Gordon AC, Garrard C, Hill AVS et al. (2016)
& Semenza GL (2007) HIF-1 regulates cytochrome Genomic landscape of the individual host response and
oxidase subunits to optimize efficiency of respiration in outcomes in sepsis: a prospective cohort study. Lancet
hypoxic cells. Cell 129, 111–122. Respir Med 4, 259–271.
78 Singer M (2014) The role of mitochondrial dysfunction 92 Textoris J, Beaufils N, Quintana G, Lassoud AB,
in sepsis-induced multi-organ failure. Virulence 5, 66– Zieleskiewicz L, Wiramus S, Blasco V, Lesavre N,
72. Martin C, Gabert J et al. (2012) Hypoxia-inducible
79 O’Neill LAJ, Kishton RJ & Rathmell J (2016) A guide factor (HIF1a) gene expression in human shock states.
to immunometabolism for immunologists. Nat Rev Crit Care 16, R120.
Immunol 16, 1–23. 93 Shalova IN, Lim JY, Chittezhath M, Zinkernagel AS,
80 Tannahill GM, Curtis AM, Adamik J, Palsson- Beasley F, Hernandez-Jimenez E, Toledano V,
Mcdermott EM, McGettrick AF, Goel G, Frezza C, Cubillos-Zapata C, Rapisarda A, Chen J et al. (2015)
Bernard NJ, Kelly B, Foley NH et al. (2013) Succinate Human monocytes undergo functional re-programming
is an inflammatory signal that induces IL-1beta during sepsis mediated by hypoxia-inducible factor-1a.
through HIF-1alpha. Nature 496, 238–242. Immunity 42, 484–498.
81 Poyton R & Hendrickson M (2015) Crosstalk between 94 Sch€afer ST, Frede S, Winning S, Bick A, Roshangar P,
nitric oxide and hypoxia-inducible factor signaling Fandrey J, Peters J & Adamzik M (2013) Hypoxia-
pathways: an update. Res Rep Biochem 5, 147–161. inducible factor and target gene expression are
82 Peyssonnaux C, Datta V, Cramer T, Doedens A, decreased in patients with sepsis: prospective
Theodorakis EA, Gallo RL, Hurtado-Ziola N, Nizet V observational clinical and cellular studies.
& Johnson RS (2005) HIF-1a expression regulates the Anesthesiology 118, 1426–1436.
95 Peyssonnaux C, Cejudo-Martin P, Doedens A, 107 Lee JH, Elly C, Park Y & Liu YC (2015) E3Ubiquitin
Zinkernagel AS, Johnson RS & Nizet V (2007) Cutting ligase VHL regulates hypoxia-inducible factor-1a to
edge: essential role of hypoxia inducible factor-1 in maintain regulatory T cell stability and suppressive
development of lipopolysaccharide-induced sepsis. J capacity. Immunity 42, 1062–1074.
Immunol 178, 7516–7519. 108 Clambey ET, McNamee EN, Westrich JA, Glover LE,
96 Fitzpatrick SF, Gojkovic M, Macias D, Tegnebratt T, Campbell EL, Jedlicka P, de Zoeten EF, Cambier JC,
Lu L, Samen E, Rundqvist H & Johnson RS (2018) Stenmark KR, Colgan SP et al. (2012) Hypoxia-
Glycolytic response to inflammation over time: role of inducible factor-1 alpha-dependent induction of FoxP3
myeloid HIF1a. Front Physiol 9, 1–7. drives regulatory T-cell abundance and function
97 Imtiyaz HZ, Keith B, Simon MC, Imtiyaz HZ, during inflammatory hypoxia of the mucosa. Proc
Williams EP, Hickey MM, Patel SA & Durham AC Natl Acad Sci USA 109, E2784–E2793.
(2010) Hypoxia-inducible factor 2 a regulates 109 Cho SH, Raybuck AL, Stengel K, Wei M, Beck TC,
macrophage function in mouse models of acute and Volanakis E, Thomas JW, Hiebert S, Haase VH &
tumor inflammation. J Clin Invest 120, 2699–2714. Boothby MR (2016) Germinal centre hypoxia and
98 Kiss J, Mollenhauer M, Walmsley SR, Kirchberg J, regulation of antibody qualities by a hypoxia response
Radhakrishnan P, Dudda J, Steinert G, Moira KB, system. Nature 537, 234–238.
Carmeliet P, Mazzone M et al. (2012) Loss of the 110 Abbott RK, Thayer M, Labuda J, Silva M, Philbrook
oxygen sensor PHD3 enhances the innate immune P, Cain DW, Kojima H, Hatfield S, Sethumadhavan
response to abdominal sepsis. J Immunol 189, 1955– S, Ohta A et al. (2016) Germinal center hypoxia
1965. potentiates immunoglobulin class switch
99 Guentsch A, Beneke A, Swain L, Farhat K, Nagarajan recombination. J Immunol 197, 4014–4020.
S, Wielockx B, Raithatha K, Dudek J, Rehling P, 111 Kojima H, Gu H, Nomura S, Caldwell CC, Kobata T,
Zieseniss A et al. (2017) PHD2 is a regulator for Carmeliet P, Semenza GL & Sitkovsky MV (2002)
glycolytic reprogramming in macrophages. Mol Cell Abnormal B lymphocyte development and
Biol 37, e00236-16. autoimmunity in hypoxia-inducible factor 1a-deficient
100 Peyssonnaux C, Datta V, Cramer T, Doedens A, chimeric mice. Proc Natl Acad Sci USA 99, 2170–
Theodorakis EA, Gallo RL, Hurtado-ziola N, Nizet V 2174.
& Johnson RS (2005) HIF-1a expression regulates the 112 Meng X, Gr€ otsch B, Luo Y, Knaup KX, Wiesener
bactericidal capacity of phagocytes. J Clin Invest 115, MS, Chen XX, Jantsch J, Fillatreau S, Schett G &
1806–1815. Bozec A (2018) Hypoxia-inducible factor-1a is a
101 Lodge KM, Thompson AAR, Chilvers ER & critical transcription factor for IL-10-producing B cells
Condliffe AM (2017) Hypoxic regulation of neutrophil in autoimmune disease. Nat Commun 9, 251.
function and consequences for Staphylococcus aureus 113 Hams E, Saunders SP, Cummins EP, Connor AO,
infection. Microbes Infect 19, 166–176. Tambuwala MT, Gallagher WM, Byrne A, Campos-
102 Naldini A, Morena E, Pucci A, Miglietta D, Riboldi torres A, Moynagh PM, Jobin C et al. (2011)
E, Sozzani S & Carraro F (2012) Hypoxia affects Attenuates endotoxic shock via alternative activation
dendritic cell survival: Role of the hypoxia-inducible of macrophages and IL-10 production by B1 cells
factor-1a and lipopolysaccharide. J Cell Physiol 227, sepsis is a complex condition characterized by a
587–595. systemic. Shock 36, 295–302.
103 Wobben R, H€ usecken Y, Lodewick C, Gibbert K, 114 Schindler K, Bondeva T, Schindler C, Claus RA,
Fandrey J & Winning S (2013) Role of hypoxia Franke S & Wolf G (2016) Preconditioned suppression
inducible factor-1a for interferon synthesis in mouse of prolyl-hydroxylases attenuates renal injury but
dendritic cells. Biol Chem 394, 495–505. increases mortality in septic murine models. Neprol
104 K€ohler T, Reizis B, Johnson RS, Weighardt H & Dial Transpl 31, 1100–1113.
F€orster I (2012) Influence of hypoxia-inducible factor 115 He C, Zhang W, Li S, Ruan W, Xu J & Xiao F
1a on dendritic cell differentiation and migration. Eur (2018) Edaravone improves septic cardiac function by
J Immunol 42, 1226–1236. inducing an HIF-1 a / HO-1 pathway. Oxid Med Cell
105 Perrin-Cocon L, Aublin-Gex A, Diaz O, Ramiere C, Longev 2018, 1–12.
Peri F, Andre P & Lotteau V (2018) Toll-like receptor 116 Sun H, Peng M, Lee S, Chen C & Chen W (2015)
4–induced glycolytic burst in human monocyte-derived Endotoxin-induced acute lung injury in mice is
dendritic cells results from p38-dependent stabilization protected by 5, 7-dihydroxy-8-methoxyflavone via
of HIF-1a and increased hexokinase II expression. J inhibition of oxidative stress and HIF-1 a. Environ
Immunol 201, 1510–1521. Toxicol 31, 1700–1709.
106 Barbi J, Pardoll D & Pan F (2013) Metabolic control 117 Yorulmaz H, Ozkok E, Erguven M, Ates G, Aydın I
of the Treg/Th17 axis. Immunol Rev 252, 52–77. & Tamer S (2015) Effect of simvastatin on
mitochondrial enzyme activities, ghrelin, hypoxia- 128 Cho H, Du X, James P, Liberzon E, Chakraborty AA,
inducible factor 1a in hepatic tissue during early phase Gao W, Carvo I, Signoretti S, Bruick RK, Josey JA
of sepsis. Int J Clin Exp Med 8, 3640–3650. et al. (2016) On-target efficacy of a HIF-2a antagonist
118 Besarab A, Chernyavskaya E, Motylev I, Shutov E, in preclinical kidney cancer models. Nature 539, 107–
Kumbar LM, Gurevich K, Tak D, Chan M, Leong R, 111.
Poole L et al. (2016) Roxadustat (FG-4592): 129 Asfar P, Schortgen F, Boisrame-helms J, Charpentier
correction of anemia in incident dialysis patients. J J, Guerot E, Megarbane B, Grimaldi D, Grelon F,
Am Soc Nephrol 27, 1225–1233. Anguel N, Lasocki S et al. (2017) Hyperoxia and
119 Akizawaw T, Iwasaki M, Otsuka T, Reusch M & hypertonic saline in patients with septic shock (
Misumi T (2019) Roxadustat treatment of chronic HYPERS2S ): a two-by-two factorial, multicentre,
kidney disease- associated anemia in Japanese patients randomised, clinical trial. Lancet Respir Med 5, 180–
not on dialysis: a phase 2, randomized, double-blind. 190.
Adv Ther 36, 1438–1454. 130 Demiselle J, Wepler M, Hartmann C, Radermacher P,
120 Pergola PE, Spinowitz BS, Hartman CS, Maroni BJ & Schortgen F, Meziani F, Singer M, Seegers V & Asfar
Haase VH (2016) Vadadustat, a novel oral HIF P (2018) Hyperoxia toxicity in septic shock patients
stabilizer, provides effective anemia treatment in according to the Sepsis – 3 criteria: a post hoc analysis
nondialysis-dependent chronic kidney disease. Kidney of the HYPER2S trial. Ann Intensive Care 8, 1–10.
Int 90, 1115–1122. 131 Chu DK, Kim LH, Young PJ, Zamiri N, Almenawer
121 Haase VH, Chertow GM, Block GA, Pergola PE, SA, Jaeschke R, Szczeklik W, Sch€ unemann HJ, Neary
Emil M, Khawaja Z, Sharma A, Maroni BJ & JD & Alhazzani W (2018) Mortality and morbidity in
Mccullough PA (2019) Effects of vadadustat on acutely ill adults treated with liberal versus
hemoglobin concentrations in patients receiving conservative oxygen therapy (IOTA): a systematic
hemodialysis previously treated with erythropoiesis- review and meta-analysis. Lancet 391, 1693–1705.
stimulating agents. Nephrol Dial Transpl 34, 90–99. 132 Martin DS & Grocott MPW (2013) Oxygen therapy in
122 Brigandi RA, Johnson B, Oei C, Westerman M, Olbina critical illness: precise control of arterial oxygenation and
G, De Zoysa J, Roger SD, Sahay M, Cross N, permissive hypoxemia*. Crit Care Med 41, 423–432.
Mcmahon L et al. (2016) Original investigation a novel 133 Mauermann WJ & Nemergut EC (2006) The
hypoxia-inducible factor 2 prolyl hydroxylase inhibitor anesthesiologist’s role in the prevention of surgical site
(GSK1278863) for anemia in CKD: a 28-day, phase 2A infections. Anesthesiology 105, 413–421.
randomized trial. Am J Kidney Dis 67, 861–871. 134 Girardis M, Busani S, Damiani E, Donati A, Rinaldi
123 Yamamoto H, Taguchi M, Matsuda Y, Iekushi K, L, Marudi A, Morelli A, Antonelli M & Singer M
Yamada T & Akizawa T (2019) Molidustat for the (2016) Effect of conservative vs conventional oxygen
treatment of renal anaemia in patients with non- therapy. JAMA 316, 1583–1589.
dialysis- dependent chronic kidney disease: design and 135 Pino A & Zappetti D (2017) Conservative oxygen
rationale of two phase III studies. BMJ Open 9, 1–8. therapy might be beneficial to patients in the intensive
124 Yeh C, Chou W, Chu C, So EC, Chang H, Wang J & care unit. Clin Pulm Med 24, 180–181.
Hsing C (2011) Anticancer agent 2-methoxyestradiol 136 Manresa MC & Taylor CT (2017) Hypoxia Inducible
improves survival in septic mice by reducing the Factor (HIF) hydroxylases as regulators of intestinal
production of cytokines and nitric oxide. Shock 36, epithelial barrier function. Cell Mol Gastroenterol
510–516. Hepatol 3, 303–315.
125 Mabjeesh NJ, Escuin D, Lavallee TM, Pribluda VS, 137 Karhausen J, Furuta GT, Tomaszewski JE, Johnson
Swartz GM, Johnson MS, Willard MT, Zhong H, RS, Colgan SP & Haase VH (2004) Epithelial
Simons JW & Giannakakou P (2003) 2ME2 inhibits hypoxia-inducible factor-1 is protective in murine
tumor growth and angiogenesis by disrupting experimental colitis. J Clin Invest 114, 1098–1106.
microtubules and dysregulating HIF. Cancer Cell 3, 138 Cummins EP, Seeballuck F, Keely SJ, Mangan NE,
363–375. Callanan JJ, Fallon PG & Taylor CT (2008) The
126 Zinkernagel AS, Peyssonnaux C, Johnson RS & Nizet hydroxylase inhibitor dimethyloxalylglycine is
V (2008) Pharmacologic augmentation of hypoxia- protective in a murine model of colitis.
inducible factor – 1a with mimosine boosts the Gastroenterology 134, 156–165.
bactericidal capacity of phagocytes. J Infect Dis 197, 139 Keely S, Campbell EL, Baird AW, Hansbro PM,
214–217. Shalwitz RA, Kotsakis A, McNamee EN, Eltzschig
127 Chen W, Hill H, Christie A, Kim MS, Holloman E, HK, Kominsky DJ & Colgan SP (2014) Contribution
Pavia-jimenez A, Homayoun F, Ma Y, Patel N, Yell P of epithelial innate immunity to systemic protection
et al. (2016) Targeting renal cell carcinoma with a afforded by prolyl hydroxylase inhibition in murine
HIF2 antagonist. Nature 539, 112–117. colitis. Mucosal Immunol 7, 114–123.
140 Xue X, Ramakrishnan S, Anderson E, Taylor M, myeloid cell-mediated inflammation. Cell 112, 645–
Zimmermann EM, Spence JR, Huang S, Greenson JK 657.
& Shah YM (2013) Endothelial PAS domain protein 1 148 Okumura CYM, Hollands A, Tran DN, Olson J,
activates the inflammatory response in the intestinal Dahesh S, Von K€ ockritz-Blickwede M, Thienphrapa
epithelium to promote colitis in mice. Gastroenterology W, Corle C, Jeung SN, Kotsakis A et al. (2012) A new
145, 831–841. pharmacological agent (AKB-4924) stabilizes hypoxia
141 Eltzschig HK & Eckle T (2011) Ischemia and inducible factor-1 (HIF-1) and increases skin innate
reperfusion-from mechanism to translation. Nat Med defenses against bacterial infection. J Mol Med 90,
17, 1391–1401. 1079–1089.
142 Howell NJ & Tennant D (2014) The role of HIFs in 149 Warnecke C, Griethe W, Weidemann A, J€ urgensen JS,
ischemia-reperfusion injury. Hypoxia 2, 107–115. Willam C, Bachmann S, Ivashchenko Y, Wagner I,
143 Sarkar K, Cai Z, Gupta R, Parajuli N, Fox-Talbot K, Frei U, Wiesener M et al. (2003) Activation of the
Darshan MS, Gonzalez FJ & Semenza GL (2012) hypoxia-inducible factor-pathway and stimulation of
Hypoxia-inducible factor 1 transcriptional activity in angiogenesis by application of prolyl hydroxylase
endothelial cells is required for acute phase inhibitors. FASEB J 17, 1186–1188.
cardioprotection induced by ischemic preconditioning. 150 Schaible B, McClean S, Selfridge A, Broquet A,
Proc Natl Acad Sci USA 109, 10504–10509. Asehnoune K, Taylor CT & Schaffer K (2013)
144 Eckle T, Kohler D, Lehmann R, Kasmi KCE & Hypoxia modulates infection of epithelial cells by
Eltzschig HK (2008) Hypoxia-inducible factor-1 is Pseudomonas aeruginosa. PLoS ONE 8, 1–11.
central to cardioprotection a new paradigm for 151 Clavien PA, Petrowsky H, DeOliveira ML & Graf R
ischemic preconditioning. Circulation 118, 166–175. (2007) Strategies for safer liver surgery and partial
145 Bernhardt WM, C^ampean V, Kany S, J€ urgensen JS, liver transplantation. N Engl J Med 356,
Weidemann A, Warnecke C, Arend M, Klaus S, 1545–1559.
G€unzler V, Amann K et al. (2006) Preconditional 152 Schneider M, Van Geyte K, Fraisl P, Kiss J, Aragones
activation of hypoxia-inducible factors ameliorates J, Mazzone M, Mairb€aurl H, De Bock K, Jeoung NH,
ischemic acute renal failure. J Am Soc Nephrol 17, Mollenhauer M et al. (2010) Loss or silencing of the
1970–1978. PHD1 prolyl hydroxylase protects livers of mice
146 Eltzschig HK, Bratton DL & Colgan SP (2014) against ischemia/reperfusion injury. Gastroenterology
Targeting hypoxia signalling for the treatment of 138, 1143–1154.
ischaemic and inflammatory diseases. Nat Rev Drug 153 Zhang XL, Yan ZW, Sheng WW, Xiao J, Zhang ZX
Discov 13, 852–869. & Bin Ye Z (2011) Activation of hypoxia-inducible
147 Cramer T, Yamanishi Y, Clausen BE, F€ orster I, factor-1 ameliorates postischemic renal injury via
Pawlinski R, Mackman N, Haase VH, Jaenisch R, inducible nitric oxide synthase. Mol Cell Biochem 358,
Corr M, Nizet V et al. (2003) HIF-1a is essential for 287–295.

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17424658, 2020, 8, Downloaded from https://febs.onlinelibrary.wiley.com/doi/10.1111/febs.15222 by CAPES, Wiley Online Library on [20/12/2022].

Hypoxia-inducible factors in metabolic reprogramming

Keywords Sepsis is a highly heterogeneous syndrome that is caused by an imbalanced

HIF protein regulation In the presence of low oxygen concentrations, or in

Fig. 2. Hypoxia-inducible factor activity

Table 1. Overview of the post-translational modifications of the HIFa subunits.

Molecule Post-translational modification HIF target protein References

PHD Hydroxylation of Pro402 and Pro564 in ODDD leading to HIF1a ↓ [24,25]

43 Gradin K, Takasaki C, Fujii-Kuriyama Y & Sogawa 56 Rossignol F, de Laplanche E, Mounier R, Bonnefont

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