Received: 16 June 2020 

|
  Revised: 5 September 2020 
|  Accepted: 24 September 2020

DOI: 10.1111/bcpt.13503

REVIEW ARTICLE

COVID-19: A Case for Inhibiting NLRP3 Inflammasome,

Suppression of Inflammation with Curcumin?

Ali Saeedi-Boroujeni1,2,3   | Mohammad-Reza Mahmoudian-Sani4   |
Mohammad Bahadoram4   | Arash Alghasi4

1
Department of Immunology, Faculty of
Medicine, Ahvaz Jundishapur University of
Abstract
Medical Sciences, Ahvaz, Iran Curcumin is the effective ingredient of turmeric, sometimes used as a painkiller in
2
Abadan School of Medical Sciences, traditional medicine. It has extensive biological properties such as anti-inflamma-
Abadan, Iran
tory and antioxidant activities. SARS-CoV-2 is a betacoronavirus developing severe
3
ImmunologyToday, Universal Scientific
pneumonitis. Inflammasome is one of the most important components of innate im-
Education and Research Network
(USERN), Tehran, Iran munity, which exacerbates inflammation by increasing IL-1β and IL-18 production.
4
Thalassemia and Hemoglobinopathy Studies on viral infections have shown overactivity of inflammasome and thus the
Research Center, Health Research Institute, occurrence of destructive and systemic inflammation in patients. NLRP3 inflam-
Ahvaz Jundishapur University of Medical
Sciences, Ahvaz, Iran masome has been shown to play a key role in the pathogenesis of viral diseases.
The proliferation of SARS-CoV-2 in a wide range of cells can be combined with
Correspondence
numerous observations of direct and indirect activation of inflammasome by other
Mohammad-Reza Mahmoudian-Sani,
Thalassemia and Hemoglobinopathy coronaviruses. Activation of the inflammasome is likely to be involved in the forma-
Research Center, Health Research Institute, tion of cytokine storm. Curcumin regulates several molecules in the intracellular sig-
Ahvaz Jundishapur University of Medical
nal transduction pathways involved in inflammation, including IBB, NF-kBERK1,2,
Sciences, Ahvaz, Iran.
Email: mohamadsani495@gmail.com AP-1, TGF-β, TXNIP, STAT3, PPARγ, JAK2-STAT3, NLRP3, p38MAPK, Nrf2,
Notch-1, AMPK, TLR-4 and MyD-88. Due to anti-inflammatory and anti-inflamma-
some properties without any special side effects, curcumin can potentially play a role
in the treatment of COVID-19 infection along with other drug regimens.

KEYWORDS
acute lung injury, acute respiratory distress syndrome, COVID-19, Curcumin, inflammasome,
inflammation, NLRP3, SARS-CoV-2

1  |   IN T RO D U C T ION destructive and severe inflammation is the leading cause of

As of 6 September 2020, the SARS-CoV-2 virus has infected
more than 27 million people and left more than 800 000 vic-
tims. According to statistics, a high percentage of patients
with COVID-19 recover and only a small percentage of
them succumb to death. Studies have documented the im-
portant role of the immune system in determining the fate
of COVID-19 patients. Observations have so far shown that
death in patients with COVID-19.1 Significant increases in
the levels of inflammatory cytokines (TNF, IL-1β, IL-6, IL-
8), colony-stimulating factors (G-CSF and GM-CSF) and in-
flammatory chemokines (MCP1, IP10 and MIP1α) and the
destructive role of inflammatory monocytes and macrophages
indicate the role of inflammation in COVID-19 pathogene-
sis.2,3 Acute respiratory distress syndrome (ARDS) and cy-
tokine storm are the two main causes of severe COVID-19.1

© 2020 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society)

Basic Clin Pharmacol Toxicol. 2021;128:37–45.  |

wileyonlinelibrary.com/journal/bcpt     37
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38      SAEEDI-BOROUJENI et al.
Recently, Liao et al, using single-cell RNA sequencing,
examined patients' bronchoalveolar lavage fluid and found
very interesting findings. In patients with severe disease, the
study found that lung tissue-resident alveolar macrophages
were removed, and instead, monocyte-derived inflammatory
macrophages were accumulated in the lungs. The inflamma-
tory macrophages, by expressing various chemokines and
cytokines, predispose the recruitment of other inflammatory
cells to lung tissue and the occurrence of ARDS.4 Curcumin
is an active ingredient in the rhizome of turmeric, Curcuma
longa, with the chemical name of diferuloylmethane and the
chemical formula of C21H20O6.5 Curcumin, which forms
about 2%-8% of turmeric compounds, is a major factor in
the yellow and golden colour of turmeric and has also been
identified as responsible for many of the properties of tur-
meric.6,7 In 1815, curcumin was first extracted and purified
from turmeric; in 1910, the structure of curcumin was intro-
duced as diferuloylmethane, which is composed of two aryl
buten-2-one (feruloyl) chromophores joined by a methylene
group.6 Curcumin is a lipophilic fluorescent molecule with
phenolic groups and conjugated double bonds.8 Curcumin
has low intrinsic toxicity but has a wide range of pharma-
cological activities, including antioxidant, anti-inflammatory
and antimicrobial properties.8 Other activities reported for
curcumin include lowering blood lipids, protecting the liver,
inhibiting lipoxygenase, inhibiting cyclooxygenase, inhibit-
ing proteases, eliminating free radicals, inhibiting lipid per-
oxidation, reducing platelet aggregation, improving digestion
by increasing bile flow and modifying cytokines and other
inflammatory agents.9 It has been shown that many chronic
diseases are caused by an imbalance of inflammatory reac-
tions.10 Recent scientific evidence suggests that turmeric,
and especially curcumin, is highly anti-inflammatory. It is
not surprising, then, that turmeric and curcumin are used to
treat many inflammatory diseases.11 In this article, we review
and summarize the existing evidence on the effects of cur-
cumin on inflammation factors and especially inflammasome
in various diseases and also its effects on adaptive immunity
and cytotoxic T cell function, ultimately demonstrating that
curcumin can potentially contribute to the treatment of pa-
tients with severe COVID-19 infection by preventing cyto-
kine storm-induced damage.
1.1  |  A body of literature
1.1.1  | Anti-inflammatory
effects of curcumin
The normal anti-inflammatory properties of curcumin are
similar to those of steroid drugs and non-steroidal anti-
inflammatory drugs, which have many side effects.12 The
anti-inflammatory properties of curcumin are attributed to
inhibition and suppression of prostaglandin synthesis and
inhibition of COX2, LOX, iNOS and inhibition of cytokine
production and transcription factors.13 Clinical studies have
shown that curcumin prevents COX2 expression.14 Dietary
curcumin significantly prevents the release of phospholipase
A2 in the colon mucosa and tumours, leading to the release of
arachidonic acid from phospholipids and changes in COX2
and LOX activity and improving prostaglandin E2 (PGE2)
levels.15 Unlike COX2 inhibitors, which reduce the catalytic
activity of the COX enzyme, curcumin reduces COX2 ex-
pression at the transcriptional level.16 The effective dose of
curcumin inhibits the two mediators of COX2 induction, in-
cluding bile acid (BA) and phorbol 12-myristate 13-acetate
(PMA).17 The researchers found that the exposure of cancer
cells to curcumin not only inhibited the cell growth, but also
reduced the level of time-dependent mRNA COX-2 and the
dose used.18 Curcumin is a safe natural inhibitor of COX2
expression in RAW264.7 cells stimulated by lipopolysaccha-
rides and interferon gamma.19 The effects of curcumin have
been studied on the nuclear factor-kB (NF-κB), which is a
protein complex that controls DNA transcription, is found
in almost all species of animal cells and is responsible for
cellular responses to stimuli. Research data showed that
curcumin inhibited the NF-kB activity in cells.20 Oxidative
stress activates DNA and NF-kB binding. Because curcumin
is known as an antioxidant, it inhibits DNA binding to NF-kB
by inhibiting oxidative stress.21 Curcumin is reported to in-
hibit IκB kinase. Curcumin ultimately prevents the transfer
of NF-kB to the nucleus. Curcumin also exhibits strong anti-
oxidant behaviour by regulating the expression of genes ac-
tivating the API and NF-kB proteins.22 Curcumin suppresses
interleukin-6 (IL-6) activity by downregulating the STAT3.23
The compound also inhibits TGF-β1 and reduces the produc-
tion levels of pro-inflammatory cytokines such as TNF-α and
MPC-1.24,25 Some researchers have suggested that TGF-β
might be a good therapeutic target for COVID-19. For exam-
ple, studies carried out by Al-helfawi et al26 and Chen27 have
reported that TGF-β inhibition can contribute to the treatment
of COVID-19. Upon entering the cell, coronaviruses corrupt
the cellular replication mechanism, causing cellular machin-
ery to replicate them. They also manipulate cell cycle arrest
through the up-regulation of TGF-β production. In the case
of SARS coronavirus, this up-regulation is done by nucle-
ocapsid protein and papain-like protease (PLpro).28 Tests of
lung samples taken from SARS patients have demonstrated
this TGF-β overexpression. In one study where TGF-β ex-
pression was suppressed by OT-101, viral replication assays
showed reduced SARS-CoV-1 and SARS-CoV-2 replica-
tion.29 It is probable that the impact of OT-101 on TGF-β can
be exploited to prevent respiratory crises in COVID-19 pa-
tients. The anti-inflammatory effects of curcumin have been
demonstrated in many studies. Because oxidative stress leads
to chronic inflammatory diseases, the antioxidant compounds
SAEEDI-BOROUJENI et al.
can be helpful in preventing and treating inflammatory dis-
orders.30 Curcumin has a high antioxidant activity. It is not
easy to answer the question of whether the anti-inflammatory
activity of curcumin is dependent on its antioxidant activity.
Since many of the previously identified antioxidants have no
anti-inflammatory properties, it seems unlikely that the anti-
inflammatory effects of curcumin are due solely to its anti-
oxidant properties.
2  |   IN F LA M MA S OME
The inflammasomes are of the most important components of
innate immunity, which enhances inflammation by increas-
ing the production of IL-1β, IL-18 and gasdermin D. The in-
flammasomes play a key role in the pathogenesis of many
diseases associated with destructive inflammation. In the
viral infections, numerous studies have shown an excessive
activity of inflammasome, resulting in destructive and sys-
temic inflammation in patients. The NLRP3 inflammasome
has been shown to play a key role in the pathogenesis of viral
diseases.31-33 The proliferation of SARS-CoV-2 in a wide
range of cells can be combined with numerous observations
of direct and indirect activation of inflammasome by other
coronaviruses. Activation of the inflammasome is likely to
be involved in the formation of severe cytokine storm, which
subsequently causes ARDS and MODS and ultimately leads
to death. Recent studies emphasis on the key role of NLRP3
inflammasome in immunopathogenesis of severe COVID-
19 especially in patients with increased risk (ex diabetes and
obesity).34-36 Curcumin activates nuclear factor erythroid
2-related factor 2 (NRF2). The Nrf2 is a transcription fac-
tor that increases the expression of a number of antioxidant
proteins under stress. This transcription factor is highly ex-
pressed in the lungs, heart, liver, brain and kidneys.37 One
of the functions of Nrf2 is to inhibit the activity of NLRP3
inflammasome as a basic signalling complex in exacerbating
inflammation.38
2.1  |  Effect of curcumin on T Cell Activation
Many COVID-19 patients experience not only severe lym-
phopenia but also a phenomenon called T cell exhaustion,
which involves the loss of function in cytotoxic T cells.39,40
Clinical trials are currently underway to address this prob-
lem through immunotherapy methods such as anti-PD1 and
PDL1 monoclonal antibodies.41 While cytotoxic T cell ex-
haustion is commonly observed in tumour microenviron-
ments and chronic viral diseases, several recent studies
have detected this phenomenon in COVID-19 patients.40,41
It has been shown that curcumin can effectively prevent
cytotoxic T cell exhaustion. There is evidence suggesting
|
     39
that curcumin can inhibit T cell loss, contribute to the im-
provement of central memory T cell/effector memory T
cell populations and the reversal of type-2 immune bias
and help maintain T cell proliferation in tumour hosts. But
curcumin may also reduce the suppressive activity of Treg
cells through the down-regulation of TGF-β and IL-10 syn-
thesis. Research has also shown that curcumin treatment
can improve the anti-cancer cell function of effector T
cells.42
2.2  |  Effect of curcumin on inflammasome
activity in the liver
Excessive consumption of fructose causes high prevalence
of metabolic syndrome and inflammatory liver disease. A
study investigated the therapeutic effects and basic molecular
mechanisms of curcumin and allopurinol in fructose-induced
liver inflammation. Data from these animal and liver models
showed that curcumin and allopurinol improved metabolic
symptoms caused by fructose, especially liver inflammation
in rats. Studies in the liver of fructose-fed rats and BRL-3A
and HepG2 cells exposed to fructose have clearly shown a
reduction in miR200a. TXNIP is a NLRP3 inflammasome
activator. The miR200a directly targets 3'UTR-rTXNIP, so
reducing it increases TXNIP expression and ultimately in-
creases the activation of NLRP3 inflammasome in BRL-3A
cells. This study demonstrated how curcumin is able to help
inhibit inflammation by inhibiting NLRP3 inflammasome
through epigenetic changes.43
2.3  |  Effect of curcumin on inflammasome
activity in the inflammatory diseases
One of the inflammatory diseases is colitis. The destructive
role of inflammatory macrophages, neutrophils, TH17 lym-
phocytes and chemokines and inflammatory cytokines has
been well demonstrated in this disease.44 The activation of
NLRP3 inflammasome also plays a role in colitis pathogen-
esis.45 A study evaluated the protective role of curcumin in
dextran sulphate sodium (DSS)-induced colitis. Curcumin
causes a decrease in IL-1β secretion and a decrease in cas-
pase-1 activation in DSS-stimulated macrophages, which is
a reason for inhibition of NLRP3 inflammasome. Curcumin
inhibits K (+) efflux, intracellular ROS production and cath-
epsin B release, all three of which are important factors in ac-
tivating the NLRP3 inflammasome. Curcumin significantly
reduces the expression of multiple inflammatory cytokines
and chemokines including IL-1β, IL-6, MCP-1 and MPO
activity, caspase-1 activity and tissue damage in the DSS-
induced colitis model.46 In a study, the therapeutic effects
and mechanism of action of curcumin in osteoarthritis were
 |
40      SAEEDI-BOROUJENI et al.
studied as one of the inflammatory diseases. The adminis-
tration of curcumin significantly reduced the progression of
osteoarthritis in the model of destabilization of the medial
meniscus (DMM). Curcumin suppresses the mRNA expres-
sion of pro-inflammatory mediators in articular cartilage in
the rats undergoing surgery. In the LPS and ATP-stimulated
THP-1 macrophages, curcumin significantly suppresses
IL-1β and TNF-α expression at both RNA and protein levels.
Compared with the control group, curcumin increases pro-
caspase-1 expression and decreases active caspase-1 expres-
sion.47 The deposition of monosodium urate (MSU) crystals
within the synovial joints causes a type of gouty arthritis
with severe inflammation. The MSU crystals are one of the
NLRP3 inflammasome activators.48 The immunopathogen-
esis of this disease is similar to COVID-19 due to the role
of inflammatory cells, especially macrophages, infiltration
of inflammatory cells, increased production of ROS and es-
pecially the activation of NLRP3 inflammasome. A study
examined the effect of the natural compound curcumin on
the MSU crystal-stimulated inflammatory response. The
treatment of MSU-stimulated THP-1-derived macrophages
was able to reduce the expression of downstream inflamma-
tory genes such as IL-1β, IL-6, TNF-α, COX-2 and PGE2
by inhibiting the NF-kB signalling pathway. In addition, cur-
cumin has been shown to reduce the mitochondrial damage
caused by MSU in THP-1 and RAW264.7 cells by prevent-
ing mitochondrial membrane potential reduction, decreasing
mitochondrial ROS and inhibiting the activity of NLRP3 in-
flammasome in these cells. Intraperitoneal administration of
curcumin reduced MSU crystal-induced paw and ankle joint
swelling in mouse models of acute gout. Curcumin applies
these effects by inhibiting NLRP3 inflammasome, reduc-
ing phosphorylation of NF-kB subunits (p65 and p50) and
inhibiting the degradation of IκBα and ultimately inhibiting
inflammation.49
2.4  |  Effect of curcumin on inflammasome
activity in the neurological diseases
Epilepsy is a chronic neurological disorder that affects about
50 million people worldwide. Numerous evidences have
shown the role of inflammation in the pathogenesis of this
disease.50 In order to investigate the effect of curcumin on
epilepsy and its basic mechanism, the rats of this disease
model were treated with curcumin, which led to the improve-
ment of cognitive impairment and Kainic acid (KA)-induced
epilepsy. The findings showed that the inflammasome activa-
tion plays a key role in the immunopathogenesis of the dis-
ease. The stimulation with KA increases the expression of
IL-1β and NLRP3, both of which have been reduced by cur-
cumin treatment. Thus, these studies showed that curcumin,
by inhibiting NLRP3 inflammasome, was able to reduce the
severity of epilepsy as well as neurodegeneration in the hip-
pocampus by inhibiting destructive inflammation.51 Another
study evaluated the function of curcumin on the hippocam-
pus exposed to glutamate neurotoxicity. Glutamate increases
ROS production, enhances endoplasmic reticulum stress and
activates NLRP3/TXNIP inflammasome, thereby resulting in
hippocampal damage. The results of this study showed that
curcumin reduces the severity of glutamate neurotoxicity by
inhibiting the activation of TXNIP/NLRP3 inflammasome
associated with ER stress through the regulation of AMPK.
Curcumin reduces TXNIP expression and prevents the cas-
pase-1 activation and IL-1β secretion.52 Neuropathic pain
is associated with destruction or disruption of the nervous
system, whether peripheral or central nerves. It is a chronic
pain that many patients suffer from. The cause of these pains
is various factors such as neuritis. A study investigated the
therapeutic effects of curcumin on improving pain in rats.
The results of these studies showed that curcumin is able
to help improve conditions by inhibiting NLRP3 inflamma-
some activation and inhibiting JAK2-STAT3 signalling path-
way in spinal astrocytes. In addition, the curcumin injection
was able to prevent an increase in spinal IL-1β. The results
of these studies clearly show how curcumin is able to help
improve a pathogenic condition by inhibiting the NLRP3
inflammasome.53
2.5  |  Effect of curcumin on the inhibition of
LPS-stimulated inflammasome
Curcumin inhibits inflammation in macrophages derived from
LPS-stimulated bone marrow by suppressing the activation of
inflammasome. In addition, curcumin has been shown to inhibit
the activation of NLRP3 inflammasome, rather than NLRC4
inflammasome or AIM2 inflammasome. Curcumin is able to
inhibit the activity of NLRP3 inflammasome by inhibiting K
(+) efflux, preventing mitochondrial instability, inhibiting ASC
oligomerization and inhibiting speckle formation. In addition to
the above, ROS, autophagy, Sirtuin-2 and acetylated alpha-tu-
bulin are the targets used by curcumin to inhibit inflammasome.
The inflammasome activation requires two signals; the first sig-
nal increases the expression of the components involved, and
the second signal stimulates the formation of the inflamma-
some complex. A study found that AI-44, as a curcumin ana-
logue, was able to prevent NLRP3 inflammasome activation
by inhibiting the second signal. The findings show that AI-44
binds to PRDX1, increasing PRDX1 interaction with pro-cas-
pase-1. It is important to note that PRDX1 prevents pro-CASP1
binding to ASC, thereby suppressing NLRP3 inflammasome
activation. As a result, AI-44 prevents caspase-1 activation and
IL-1β secretion. Knocking down PRDX1 significantly elimi-
nates the inhibitory effect of AI-44 on the NLRP3 inflamma-
some. Importantly, AI-44 reduces LPS-induced endotoxemia
SAEEDI-BOROUJENI et al.
by suppressing NLRP3 activation in rats.54 A study examined
the effects of curcumin on the S-glutathionylation of NLRP3
induced by CNC-AEMA2 in LPS-primed mouse macrophages
(J774A.1), as well as interactions among proteins of the NLRP3
inflammasome complex. This study showed that the addition of
curcumin concomitantly with LPS caused the greatest decrease
in NLRP3 S-glutathionylation and a respective increase in
caspase-1 S-glutathionylation.55 Another study found that the
administration of curcumin significantly reduced the concen-
tration of LM-derived HMGB-1 and IL-1β and improved the
survival of rats with lethal endotoxic shock. Curcumin inhibits
the NLRP3 inflammasome to some extent by suppressing the
extracellular signal-regulated protein kinase.56
2.6  |  Effect of curcumin on inflammasome
suppression in kidney diseases
A study examined the effect of curcumin on hyperuricemia
and nephritis in hyperuricemic rats. Curcumin in these rats
was able to inhibit NLRP3 inflammasome and reduce serum
levels of inflammatory cytokines such as IL-1β and IL-18. In
addition, the administration of curcumin reduced serum levels
of uric acid (UA), creatinine (CRE) and blood urea nitrogen
(BUN). At the same time, the treatment with curcumin effec-
tively inhibited serum and hepatic levels of xanthine oxidase
(XOD) and increased the activity of antioxidant enzymes, such
as SOD and GSH-Px.57 The rat models of chronic kidney dis-
ease (CKD) were treated with theracurmin as a new formu-
lation of curcumin to investigate the cardiovascular effects.
Theracurmin was able to improve the structural and func-
tional manifestations of heart damage along with renal failure
in these rats by inhibiting heart NLRP3 inflammasome and
subsequently inhibiting IL-1β production. The results of this
study clearly showed the destructive effect of NLRP3 inflam-
masome activation on induced renal dysfunction and its inhi-
bition as a new treatment strategy.58 Another study evaluated
the effect of curcumin on kidney disease caused by diabetes
and its mechanism of action in db/db mice. The curcumin-
treated mice showed lower incidence of renal hypertrophy,
decreased levels of mesangial matrix and thus lower albumi-
nuria. Increased protein and mRNA expression of the collagen
IV and fibronectin genes in the db/db mice renal cortex were
inhibited by curcumin therapy. In addition, the treatment with
curcumin was associated with a significant reduction in IL-1β
levels, caspase-1 cleavage and NLRP3 protein (all indicative
of inhibition of NLRP3 inflammasome) in kidney cortex of db/
db mice and in HK-2 cells exposed to high concentrations of
glucose.59 A study evaluated the anti-inflammatory effects of
curcumin extract on the expression of inflammatory transcrip-
tion factors in haemodialysis patients. Severe and problematic
inflammation in these patients, such as COVID-19, is a seri-
ous challenge. Three-month treatment of CKD patients under
|
     41
haemodialysis taking curcumin could reduce the expression of
NF-kB and hsCRP genes as inflammatory markers. This study
suggests that oral curcumin supplementation may have an anti-
inflammatory effect in this group of patients.60
2.7  |  Effect of curcumin on inflammasome
activity in lung diseases
The penetration of paraquat (PQ) (N, N′-dimethyl-4,4′-
bipyridinium dichloride) into the body causes the onset of
acute lung injury (ALI) through increased oxidative stress
and inflammation. In a study, normal human lung fibroblasts
(WI38-VA13) were treated with curcumin. In the PQ-treated
group, curcumin reduced the expression levels of TXNIP,
NLRP3, IL-1β, IL-18 and caspase-1. Curcumin effectively
prevented the increase in Notch1 without affecting the phos-
phorylation of ERK1/2. Therefore, the results of this study
showed that curcumin is able to improve the PQ-induced ALI
by effectively inhibiting NLRP3 inflammasome and prevent-
ing the increase of inflammatory cytokines.61 Curcumin has
potent anti-inflammatory properties but has a low solubil-
ity rate and is rapidly cleared in plasma. In a study, a new
water-soluble curcumin formulation of cyclodextrin complex
of curcumin (CDC) was delivered directly into the lungs of
C57BL/6 mice inoculated with a lethal dose of Klebsiella
pneumoniae. Despite the presence of bacteria in the blood
and lungs and the presence of lung injury, inflammation and
oxidative stress, the administration of CDC led to a signifi-
cant reduction in mortality rate in these mice. Curcumin re-
duced the expression of haemolysin gene, TBF-α, IFN-beta,
NLRP3, HIF-2α and NF-kB genes. These findings suggest
that curcumin has improved the severity of pneumonia by
inhibiting the activation of inflammasome as well as hypoxia
signalling pathways. At the cellular level, the CDC resulted
in reduced cell death, improved viability and protection of
human lung epithelial cells under in vitro condition.62 The
macrophages play an important role in the immunopatho-
genesis of COVID-19. In the BAL fluid, the macrophages
derived from inflammatory monocytes in the patients with
severe COVID-19 replace lung tissue-resident alveolar mac-
rophages. A highly inflammatory subtype of macrophages
appears even in the lungs of these patients. The results of
this study could strongly suggest that curcumin may be ef-
fective in helping to control inflammation in patients with
severe COVID-19.
2.8  |  Effect of curcumin on inflammasome
activity in other diseases
Rising evidence suggests that the inflammation is associated
with the pathophysiology of depression. The association
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42      SAEEDI-BOROUJENI et al.
between the antidepressant effect of curcumin and its anti-
inflammatory properties was investigated in a study. The
results of this study showed that curcumin could effectively
reduce the mRNA expression of IL-1β, IL-6 and TNF-α
pro-inflammatory cytokines and suppress the NF-kB acti-
vation. Curcumin also reduces the activation of the P2X7R/
NLRP3 axis due to stress and the conversion of activated
form of IL-1β.63 The potential therapeutic value of curcumin
in systemic lupus erythematosus (SLE), as an autoimmune
disease associated with inflammation, was investigated in
a study. For this purpose, the Lupus-prone female MRL/
lpr mice were treated with curcumin. Curcumin therapy sig-
nificantly reduced proteinuria and nephritis in these mice.
The serum anti-dsDNA levels and spleen size were also re-
duced with curcumin treatment. In line with evidence from
other studies, curcumin reduced the activation of NLRP3
inflammasome in these mice. In vitro, curcumin signifi-
cantly inhibits the activity of NLRP3 inflammasome due
to anti-dsDNA+ serum in podocytes. Therefore, this study
potentially showed the therapeutic effects of curcumin in
SLE.64 Another study showed the effects of curcumin on
macrophages induced by Phorbol 12-myristate 13-acetate
(PMA) and reported that curcumin effectively reduced the
NLRP3 expression, the caspase-1 cleavage and the IL-1β
secretion in PMA-induced macrophages. The results of this
study showed that the PMA exerts its effects by activating
P2X7R. The PMA via P2X7R exerts a range of changes in
the cell and increases the expression of NLRP3 inflammas-
ome. In addition to NLRP3 inflammasome components, cur-
cumin effectively inhibits the TLR4 and MyD88 expression
and NF-kB activation and IkappaB-alpha phosphorylation.65
F I G U R E 1   Curcumin targets in inflammation and inflammasomes
The inflammation plays a destructive role in causing many
malignancies. Inflammation, for example, is a key factor in
the immunopathogenesis of malignant mesothelioma as a
disease with a disappointing prognosis and poor treatment
strategies. The therapeutic effects of curcumin on pyrop-
totic cell death of malignant mesothelioma cells as a type
of cell death associated with inflammation caused by the
activation of NLRP3 inflammasome were investigated in a
study. These studies showed that curcumin, without activat-
ing IL-1 and IL-18, destroys cancer cells by inducing ap-
optosis. Analysis of gene expression in this study using the
human inflammasome pattern showed that curcumin sig-
nificantly reduced the expression of genes associated with
inflammation such as NF-kB, TLR and IL-1β.66
3  |  CONCLUSION
Curcumin in inflamed organs (liver, lung, brain and kid-
neys) reduces the expression levels of NLRP3, IL-1β, IL-18
and caspase-1 and inhibits the inflammasome. Curcumin
activated Nrf2 and inhibited NF-kB. In the liver, curcumin
directly targets 3'UTR-rTXNIP with the help of miR200a
and inhibits NLRP3 inflammasome. Curcumin reduces the
severity of neurotoxicity by inhibiting the formation of
TXNIP/NLRP3 complex associated with ER stress through
the regulation of AMPK. Curcumin in LPS-stimulated
mouse macrophages inhibits the activity of NLRP3 inflam-
masome by inhibiting potassium excretion, mitochondrial
instability, ASC oligomerization and speckle formation.
In addition to the above, ROS, autophagy, Sirtuin-2 and
SAEEDI-BOROUJENI et al.
acetylated alpha-tubulin are the targets used by curcumin
in inhibiting the inflammasome. In the lungs, curcumin ef-
fectively prevented the increasing Notch1. In addition to
inflammasome components, curcumin effectively inhibits
TLR4 and MyD88 expression and IBB phosphorylation.
Curcumin has a regulatory effect on several molecules in
the intracellular signal transduction pathways involved in
inflammation, including ERK1, 2AP-1, TGF-β, TXNIP,
STAT3, PPARγ, JAK2-STAT3, p38MAPK and AMPK
(Figure 1). Curcumin down-regulates the expression of
inflammatory enzymes, such as COX2 and iNOS, inhibits
the expression of the 5-LOX pro-inflammatory enzyme and
chemokines and reduces the expression of CRP and inflam-
matory cytokines of TNF-α, IL-6 and IL-8. Studies have
shown that severe inflammation and cytokine storm in the
COVID-19 infection develop acute respiratory distress
syndrome (ARDS), acute lung injury (ALI) and multiple
organ dysfunction syndromes (MODS) such as the lungs,
liver, kidneys, brain and eventually death. Oral curcumin
supplementation may potentially play a role in inhibiting
the COVID-19 inflammation along with other drug regi-
mens by affecting these pathways and molecules and due to
applying anti-inflammatory, antioxidant and anti-apoptotic
properties without specific side effects.
CONFLICT OF INTEREST
The authors declare that they have no competing interests.
AUTHOR CONTRIBUTIONS
ASB, MMS and MB designed the study. MMS wrote the
manuscript with support from AA. The authors read and ap-
proved the final manuscript.
CONSENT FOR PUBLICATION
This article does not contain any studies with human partici-
pants or animals performed by any of the authors.
ORCID
Ali Saeedi-Boroujeni  https://orcid.org/0000-0001-6167-1412
Mohammad-Reza Mahmoudian-Sani  https://orcid.
org/0000-0002-1096-5661
Mohammad Bahadoram  https://orcid.org/0000-0002-7106-9799
Arash Alghasi  https://orcid.org/0000-0003-3482-2195
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