Journal of Oral Biosciences 64 (2022) 193e201

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Journal of Oral Biosciences

journal homepage: www.elsevier.com/locate/job

Review

Immunopathogenesis and distinct role of Th17 in periodontitis: A

review
Vineet Kini b, Ipseeta Mohanty c, Gaurang Telang a, Nishant Vyas a, *
a
Logical Life Science Pvt. Ltd., Pune, India
b
Department of Pharmacology, MGM Institute of Health Sciences, Navi Mumbai, India
c
Department of Pharmacology, MGM Medical College, Navi Mumbai, India

a r t i c l e i n f o a b s t r a c t

Article history: Background: Periodontitis is a multifactorial inflammatory disease mediated by the host immune
Received 11 March 2022 response to dental plaque. Periodontitis is characterized by periodontal bone loss and loss of tooth
Received in revised form support. Several studies have corroborated the infiltration of T lymphocytes in periodontitis and
20 April 2022
correlated the infiltration with chronic inflammation in a dysregulated T cell-mediated immune
Accepted 22 April 2022
Available online 27 April 2022
response. The complexity of the disease has prompted multiple studies aiming to understand T cell-
mediated pathogenesis.
Highlight: Recent findings have demonstrated the pivotal role of helper T cells in many autoimmune
Keywords:
Periodontitis
diseases, such as rheumatoid arthritis, which has been conventionally correlated with periodontal bone
Helper T cells loss. In contrast, the roles of helper T subsets, Th1, Th2, and particularly Th17, have not been explored.
Th17 cells Th17-mediated pathogenesis is a significant aspect of the progression and therapy of periodontitis.
Cytokines Conclusion: In this review, we highlight the complex role of Th17 in the underlying pro-inflammatory
cascades mediated by a repertoire of Th17-released molecules and their role in aggravated inflamma-
tion in periodontitis. We also summarize recent therapeutics targeting Th17 and related molecules,
primarily to ameliorate inflammation and maintain periodontal care.
© 2022 Japanese Association for Oral Biology. Published by Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193
2. Immune dysregulation, inflammation, and pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194
3. Significance of Th17 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194
4. Th17/Treg plasticity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195
5. Cytokines & chemokines and associated immune cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196
6. Th17-targeted therapeutics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197
7. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198
Ethical approval . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199
Author Contribution statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199
Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199
Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199

1. Introduction
* Corresponding author.
E-mail addresses: drvinkin@gmail.com (V. Kini), ipseetamohanty@yahoo.co.in The innate immune system plays a vital component in inflam-
(I. Mohanty), gaurangtelang98@gmail.com (G. Telang), nishant@logicallifescience. mation in view of its ability to react quickly and recruit immune cells
com (N. Vyas).

https://doi.org/10.1016/j.job.2022.04.005
1349-0079/© 2022 Japanese Association for Oral Biology. Published by Elsevier B.V. All rights reserved.
V. Kini, I. Mohanty, G. Telang et al.
via cytokines such as TNFa, IL-1b, and others [1]. Furthermore, the
inflammatory conditions are either aggravated or ameliorated by the
recruitment of elements of the adaptive immune system, namely B
cells and T cells. By virtue of the variability in inflammatory mech-
anisms in a myriad of diseases, the pathways triggered and their
microenvironments differ. In addition, the innate immune system
participates in triggering chronic inflammatory conditions, which in
turn induces an adaptive immune response. The adaptive immune
response is slower in relation to innate immune response, although
its specificity and regulatory as well as effectors functions maintain
delicate homeostasis to ensure unaltered health of an individual [2].
Cell-mediated immunity is of paramount importance as T cell-
mediated apoptosis plays a vital role in inflammatory conditions.
Inflammation is usually caused by invasion of pathogens or trauma
to tissues which are usually self-limiting and subsides following the
elimination of causative agents. Nevertheless, alteration of the im-
mune response during inflammation may lead to acute inflamma-
tion and has the potential to transition to chronic inflammation.
Due to the inflammatory characteristics of periodontitis and its
high prevalence, nearly 70% of all adults with dentate adults suffer
from this disease [3,4]. Periodontitis is an inflammatory disease of
the tooth-supporting tissues characterized by progressive peri-
odontal attachment loss and bone loss. Periodontitis is caused due
to a host-mediated inflammatory disease in response to dental
plaque and can have an onset at any age, but the rate of progression
of the disease is subject to the type of immune response leading to
periods of exacerbation and quiescence.
The periodontal disease thus initiated by dental plaque leads to
a progression from inflammation of the gingiva, i.e., gingivitis, to-
wards the involvement of the inflammation of the tooth-
supporting periodontal tissues leading to attachment loss and
periodontal bone loss leading to immune response. Primarily, T
cell-mediated immune response is vital for the fate of inflammation
and subsets of T cells; Cytotoxic T cells (Tc), regulatory T cells (Treg),
and helper T cells (Th) maintain anti-inflammatory together with
pro-inflammatory immune responses. However, skew in this deli-
cate balance may cause autoimmune reactions, thereby aggravating
inflamed tissue and promoting tissue deterioration. Thereby it is
critical to understand and deduce the mechanisms involved in this
common inflammatory disease to develop new and improved
therapies to restore or ameliorate immune disequilibrium.
We outlined the critical function of Th17 cells in periodontitis, as
well as how transcription factors, cytokines, and chemokines in-
fluence them. We also conclude that Th17 cells are heterogeneous
and plastic. Current therapeutics that target Th17 cells are also
highlighted. We also discuss recent advances in Th17-targeted
therapies as well as their prospects.
2. Immune dysregulation, inflammation, and pathogenesis
Due to technological developments and the use of in vivo
models to examine the function of the immune system in chronic
inflammatory disorders like periodontitis, our understanding of
periodontitis has substantially advanced in the last decade. Peri-
odontitis was once thought to be caused solely by restricted strains
of microbial pathogens, but later research revealed otherwise, with
more and more evidence pointing to the participation of compli-
cated processes and causes other than microbial infections [5,6].
The pathogenesis of periodontitis originates from gingivitis with an
increasing degree of inflammation.
The progression of gingivitis to periodontitis is largely owing to a
dysregulated immune response in the oral cavity, which is always
under stress as a result of frequent contact with external pathogens.
The balance between local inflammation and suppression keeps the
oral cavity healthy under normal conditions [7,8]. Gingivitis is
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Journal of Oral Biosciences 64 (2022) 193e201
generally caused by a rise in the population of commensal bacteria,
which is usually reversible with timely intervention. However, in
certain patients, gingivitis may progress to periodontitis because of
varying degrees of susceptibility. Surprisingly, chronic gingival
inflammation leads to the creation of lesions or inflammatory pockets,
which provide microorganisms with sustenance via gingival crev-
icular fluid (GCF). Because of its composition, which contains serum
transudate, disintegrating cells, and inflammatory exudates, this
nutrient-rich GCF provides great growth and support [6,9]. This pro-
vides an ideal habitat for anaerobic bacteria to thrive, resulting in
dysbiosis. This, in turn, exacerbates inflammation, and the dysregu-
lated immune response, when combined with the chronic inflam-
matory state, enhances dysbiosis, which encourages bacterial
development [10,11].
Furthermore, this is not the only pathogenic process in peri-
odontitis, since several investigations in mice have revealed a
bacterial-independent mechanism [12]. Other factors, such as ge-
netic and environmental factors, have been found that may pre-
dispose an individual to the pathogenic change of gingivitis to
periodontitis. The G-308A (rs1800629) polymorphism of the tumor
necrosis factor (TNF-a) is connected to periodontitis risk in Asian
population research published in 2021 [13]. Similar studies con-
ducted on smokers and obese people corroborated that repeated
exposure to carcinogens increases the risk of periodontitis to 50%
and may also result in poor response to treatment in smokers, while
obese people are at an increased risk of developing periodontitis
[14,15]. Other factors such as psychological stress and anxiety may
affect therapeutic efficacy [16]. In conclusion, periodontitis is a
complex multifactorial chronic inflammatory disease mainly
caused by dysbiosis dysregulated immune system along with ge-
netic and environmental factors.
3. Significance of Th17
The discovery of Th17 cells was of utmost importance in
deducing the conventional Th1/Th2 concept which was previously
had literature lacunae. The current categorization of helper T cell
subsets stems from the early work of Mosmann and Coffman in
1986 i.e; classification of Th1 and Th2 [17]. These subsets including
others emerge from CD4þ T cells under the tight regulation of cy-
tokines and transcription factors as described in Figure. 1.
Since their discovery in 2005, Th17 cells that secrete the lineage-
specific transcriptional factor retinoid-related orphan receptor
gamma t (RORgt) in addition interleukin 17A (IL-17A) have
garnered attention due to their profound correlation in the path-
ogenesis of various autoimmune diseases, for instance, rheumatoid
arthritis, psoriasis, multiple sclerosis and inflammatory bowel
disease (IBD) [18e23]. Originally named after IL-17A, Th17 subsets
are not the only producers of IL-17A, Natural killer T (NKT) cells, gd
T cells along with congenital lymphoid cells also secrete IL-17A in
response to pathogenic invasion and/or injury [24,25]. As reported
before the role of Th17 has largely been attributed to anti-fungal
response as individuals with Th17 cell abnormalities are more
vulnerable to fungal infections like Candida albicans [26].
The adaptive immune system's role in the defense of mucosal
tissues is indispensable out of which T cells play a critical role,
especially in the oral mucosa. The significance of Th17 cannot be
overlooked in periodontitis as its number surges dramatically in
patients with periodontitis and is the dominant T cell subpopula-
tion in periodontal lesions [27e29]. The reciprocal generation of
Th17 and Treg cells is critical. Maintenance of delicate Th17/Treg
balance is vital for appropriate immune response in diseased con-
ditions such as periodontitis. However, the findings regarding the
role of Th17 cells are contradictory. In vivo studies involving IL-
17RAKO mice reported severe bone loss which was attributed to
V. Kini, I. Mohanty, G. Telang et al.
Fig. 1. CD4þ T cell differentiation into Th-specific subsets under the regulation of cytokines and transcription factors. For Th1 differentiation, IFN-g and TNF-a are activated by
transcription factors STAT1 and STAT4 with T-bet under the action of IL12 and IFN-g. Similarly for Th2 differentiation IL-4, IL-5, IL-9, IL-13 are activated by transcription factors
STAT5 and STAT6 with GATA3 under the influence of IL-2 and IL-4. Furthermore, IL-17 and IL-23 are activated by transcription factors STAT3 and SMAD2/3 with RORgt under the
influence of IL-6, IL-23, and TGF-b.
atypical chemokine expression and neutrophil migration [30].
Conversely, a study on Cd4creStat 3fl/fl and LckcreRorcfl/fl mice re-
ported low alveolar bone resorption compared to the wild-type
mice [31]. The role of IL-17 is also controversial as it showed that
alveolar bone loss is correlated to abnormal chemokine production
and compromised Porphyromonas gingivalis antibody response in
female mice [32]. To further complicate the current understanding
of the Th17 subsets' role in periodontitis studies involving auto-
somal dominant high IgE syndrome (AD-HIES) patients with
congenital poor Th17 cell differentiation showed low alveolar bone
resorption and resistance to periodontitis [33,34].
4. Th17/Treg plasticity
The reciprocal generation of Th17 and Treg cells is critical.
Maintenance of delicate Th17/Treg balance is vital for appropriate
immune response in diseased conditions such as periodontitis. A
myriad of factors such as In the production and preservation of
these cells, costimulatory signals, cytokine signals, TCR signals,
Foxp3 stabilization, metabolic processes, and microbiota are all
critical in inflammatory settings [35]. The mutually antagonistic
nature of Tregs is evident and has pathological significance in
periodontitis as evident by the gingival biopsies revealing increased
expression of CTLA-4, GITR, CD103, CD45RO, and FOXP3 by
CD4þCD5þCDTLA4þ cells [36]. Several studies have investigated the
role of Tregs in periodontitis where increased Treg infiltration of
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Journal of Oral Biosciences 64 (2022) 193e201
gingival tissue and immune suppression was reported in experi-
mental periodontitis induced by Aggregatibacter actino-
mycetemcomitans [37]. Additionally, Alvarez et al. provide an
interesting perspective on the role of Tregs in the pathogenesis of
periodontitis by reporting that Foxp3 levels decline rapidly in cer-
vical lymph node Tregs and aid Th17 mediated pathogenesis.
Furthermore, they also provide a novel perspective on Th17 that
mediated bone loss that excessive Th17 response can be attributed
to the fact that destruction of pathogenic microbes' habitat [alve-
olar bone] aids in containing the extent of microbial invasion.
Moreover, the origin of Th17 cells accumulating in the periodontal
lesions was reposted to be non-intestinal origin suggesting local
expansion or differentiation of Th17 under a pro-inflammatory
microenvironment in periodontitis in mice [38].
The role of IL-6 is significant in regulating the delicate balance of
Th17 and Treg by directly inducing Th17 differentiation along with
TGF-b from naïve T cells as well as in absence of TGF-b this differ-
entiation results in IL-17þFOXP3þ cells or IL-17 producing Tregs
[39e41]. Curiously, these exFoxp3 Th17 cells, a group of Th17 cells
that formerly expressed Foxp3 but subsequently lost it, have now
been linked to the detection of IL-6. Additionally, the manifestation
of IL-17þFOXP3þ cells implies possible transdifferentiation of Treg
into Th17 cells, thereby promoting inflammatory cascades primar-
ily these exFoxp3 Th17 cells produce considerably higher
membrane-bound RANKL than conventional Th17 cells and are
drastically more pathogenic [38,42]. This finding has been
V. Kini, I. Mohanty, G. Telang et al.
corroborated by a 2014 study on the adoptive transfer of exFoxp3
Th17 cells into mice leading to the decrease of FOXP3 expression in
the majority of transplanted T cells exacerbating the onset and
severity of arthritis in mice [43]. In contrast, mucosal-associated
invariant T (MAIT) cells are closely linked with the immune
sensing of bacteria and have been reported that there is a sub-
stantial but strong negative association between bacterial taxa,
particularly those that express the riboflavin pathway, and the
production of IL-17 and Va7.2-Ja33, suggesting that the host MAIT
cell defense mechanism is elevated [44,45]. Both the sub-
populations exFoxp3 Th17 and MAIT cells have been reported to be
present in periodontal lesions and show their participation in a
complex inflammatory microenvironment with the pathogenic
invasion of microbes. Although further studies are required to
completely understand and elucidate the signaling mechanisms
and pathogenic mechanisms employed by these cells.
5. Cytokines & chemokines and associated immune cells
Polarizing cytokines activate distinct transcription factor (TF)
cascades within naïve CD4þ T cells, further influencing T cell dif-
ferentiation into distinct effector T cell subtypes. The effector sub-
sets are Th1, Th2, and Th17 which are characterized by the
expression of distinct transcription factors, namely RORgt, GATA3,
and T-bet, respectively, that drive the production of signature
effector cytokines specific to each Th subset (Fig. 2). These effector
cytokines are essential in mediating responses to an array of
pathogens [46,47].
The primary cytokine secreted by Th17 cells is IL-17A which has
a limited but powerful ability to induce inflammation via syner-
gistic effects as IL-17A acts on multiple cells such as epithelial cells,
endothelial cells, and fibroblasts [15,48,49]. Many studies have
shown that IL-17A exacerbates inflammation by promoting the
expression of GCSF, GM-CSF, TNF-a, and IL-1b, IL-6, IL-8 [19,21].
Moreover, IL-17A recruits monocytes and neutrophils by various
chemokines including and not limited to CCL2, CXCLI, CXCL2,
CXCL5, CXCL8 [50,51]. The primary cytokine driving osteoclasto-
genesis is RANKL, whereas OPG, which acts as a decoy receptor for
RANKL, is a powerful inhibitor of osteoclast differentiation. In
periodontal ligament cells, IL-17A has been shown to boost RANKL
expression while inhibiting OPG expression, which might explain
why Th17 cells promote alveolar bone loss [52].
Furthermore, many studies have reported an increased level of
IL-21 in saliva as well as serum of periodontitis patients and also
showed a decrease in levels after treatment which highlights its
role in the pathogenesis of periodontitis [53,54]. Additionally, the
synergistic effect of IL-21 and TGF-b in absence of IL-6 promotes the
Th17 development and activation via STAT3 and inhibits the
expression of FOXP3 [55,56].
Although some studies have found a correlation between IL-21
and RANKL expression in severe periodontitis, the exact mecha-
nism needs to be elucidated as human epithelial and endothelial
cells lack the surface expression of IL-22r [57e59]. Nevertheless,
some evidence exists regarding the pro-inflammatory effects of IL-
22 such as enhancing the expression of TNF-a, IL-17, and MMP-I
[60e63].
The role of GM-CSF is interesting as it acts on dendritic cells and
monocytes in turn promoting the expression of IL-6 and IL-23
thereby participating in the differentiation of Th17 cells, here the
IL-23 promotes the production of GMCSF forming a positive feed-
back loop [64].
Curiously, all Th17 subsets do not enhance inflammation by IL-
17A. The heterogeneity incases of Th17 cells point towards varying
levels of pathogenicity such as immunoregulatory IL-10þ Th17 and
pro-inflammatory Th17 cells [65,66]. Th17 possesses the exclusive
196
Journal of Oral Biosciences 64 (2022) 193e201
ability to transdifferentiate into other non-Th17 phenotypes under
the influence of a myriad of cytokines, this ability is termed Th17
plasticity [66]. The TGF-b1þIL-6 induced Th17 cells provide the
majority of current information on Th17 cells [67]. The cytokines IL-6,
IL-23, and TGF-1 all play imperative roles, whereas the participation
of IL-21 in Th17 polarization remains uncertain in vivo. This is
corroborated by studies performed on IL-21/ or IL-21R/ mice
with experimental autoimmune encephalomyelitis (EAE) [68,69],
implying the insignificant function of IL-21 signaling mediated Th17
development. Th17 cells induced by TGF-b1þIL6 exhibit pro-
inflammatory response to some extent; they are generally regar-
ded as non-pathogenic Th17 cells contrastingly (Fig. 3), demon-
strating protective functions in precise settings [70e73]. These non-
pathogenic Th17 cells secrete IL-4 and IL-10, which have regulatory
functions along with IL-9, CD5L (CD5-like molecule), and GATA3,
which are negative regulators of pro-inflammatory immune
response [72,74e76]. Recently a novel Th17 phenotype, CXCR3þ
Th17 cells also known as TH17.1 cells occurring under the regulation
of IL-12 and IL-23 has been identified, this discovery may pave the
way for a deeper understanding of Th17 plasticity [77]. The primary
difference between the newly identified Th17.1 and classical
Th17 cells is the expression of IL-17A where the former differentiates
into IL-17Aþ IFN-gþ cells or IL-17A IFN-gþ cells [78]. These cells
exhibit a high degree of pro-inflammatory properties including
upregulated GM-CSF, CCL20, and IL22 production resulting in strong
TCR stimulation leading to elevated proliferative ability [79,80]. A
recent study suggests the role of P.gingivalis aiding dysbiosis where
the slow increment of IL-17A in early-stage and elevated expression
of IFN-g in later stage helps in the transition of classic Th17 cells into
exTh17 cells occurring due to conversion from acute to chronic
inflammation [81].
In order to understand the complex pathogenesis of periodon-
titis, the role of immune cells such as neutrophils and antigen-
presenting cells (APCs) is indispensable. These cells work in syn-
ergy with Th17 and aid in the inflammatory response and enhance
the disease severity such as the accumulation of neutrophils re-
ported in the periodontium [82,83]. Neutrophils unleash a salvo of
inflammatory factors not limited to reactive oxygen species (ROS)
and MMPS but also chemokines CCL2 and CCL20 which lead to Th17
recruitment to the inflamed site, and synergistic inflammatory
response directly damaging connective tissue and inducing bone
resorption [84e86]. Additionally, the expression of CCL20 is
increased in gingival fibroblasts resulting from the cooperation of
IL-17 and IL-Ib aiding in the recruitment of more Th17 [87]. The
feedback loop is formed by Th17 -induced GM-CSF which recruits
neutrophils further leading to mutual recruitment.
In addition to neutrophils, many studies have reported that APCs
play a significant role since they are stimulated by pathogens, these
activated APCs facilitated Th17 proliferation by upregulating in-
flammatory markers [88,89]. The adaptive immune system is
mediated by dendritic cells and Th17 differentiation is regulated by
the involvement of monocytes and macrophages which is evident
by their increased number in patients with periodontitis [90].
Moreover, the major periodontal pathogen P.gingivalis is recognized
by monocytes via toll-like receptors (TLR2/4) and leads to upre-
gulation of IL-Ib, IL-23, and Delta-like ligand 4 (Dll-4), which is a
direct result of stimulation by P.gingivalis lipopolysaccharide (LPS)
while leading to Th17 differentiation and activation [91,92].
Furthermore, the alveolar bone resorption which is a characteristic
of periodontitis is also the result of a cascade of inflammatory
response where the upregulation of CD86 expression induces
monocyte differentiation into macrophages leading to an increase
in the expression of CCR7 by the macrophages and secretion of IL-6
and IL-23, which stimulate the expansion of naïve T cells into
Th17 cells and proliferation of osteoblasts [91,93,94].
V. Kini, I. Mohanty, G. Telang et al.
Fig. 2. The differentiation of pathogenic (pro-inflammatory phenotype) Th17 subset under the influence of cytokines IL-1b, IL-6, IL-23, and TGF-b1 which work in various com-
binations to also generate non-pathogenic phenotype from naive CD4þ T cells.
The pathogenesis of periodontitis is strongly influenced by the
primary pathogen P.gingivalis which is a gram-negative anaerobic
bacteria and as a pathogen, it co-operates with APCs which in turn
induces the activation of Th17 cells [89,95,96]. The immune
response of the Th17 subset is reinforced by inflammatory cyto-
kines IL-Ib, IL-17, IL-23, and others as a direct result of activation of
dendritic cells by P.gingivalis [96]. The reason the P.gingivalis has
such a profound significance in pathogenesis is that P.gingivalis LPS
has shown to directly induce Th17 differentiation in-vitro via TLR2
signaling and promoting bone resorption by IL-17 through upre-
gulation of RORC [97,98]. The strains of P.gingivalis have been
classified into virulent (W83) and avirulent (ATCC33277) differing
in their ability to induce Th17 differentiation [96,98].
6. Th17-targeted therapeutics
The paramount importance of Th17 in periodontitis is undeni-
able and this has led to many therapies targeting Th17 cells and
related molecules. Here we report some experimental therapies
targeting Th17 and their modulators. The primary cytokine of Th17
is IL-17 which is a natural target to counter the Th17-mediated
inflammation and has shown promise in mice where suppression
of IL-17 reduced alveolar bone loss [99]. In vivo models of alveolar
bone resorption induced by GSK805 or curcumin have shown
positive results upon targeting RORgt and downregulating IL-17
expression [33,99]. This strategy has been successful in other IL-
17A-related autoimmune diseases such as psoriasis as a phase III
clinical trial of mAB against IL-17RA, Brodalumab showed 70% of
patients achieved a 75% decrease in psoriasis area severity index at
12 weeks [100,101]. Another study reported impaired chemokine
expression and neutrophil migration resulted in significant alveolar
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Journal of Oral Biosciences 64 (2022) 193e201
bone loss in IL-17RAKO mice [102]. Additional studies are due in this
strategy of targeting IL-17/IL-17R to elucidate exact mechanisms
and clinical trials are required to verify the in vitro and in vivo
successes.
As known the expansion and survival of Th17 cells are main-
tained by IL-6 and IL-23 making them a more suitable therapeutic
target [103]. Tocilizumab (TCZ) is a recombinant humanized
monoclonal antibody that suppresses IL-6 signaling by binding to
human IL-6R [104]. Patients who received TCZ treatment had less
periodontal inflammation than those who did not receive TCZ
treatment [105,106]. Furthermore, for IL-23 a patient with LAD-I,
systemic administration of ustekinumab, a monoclonal antibody
that blocks the p40 component of IL-23, reduced inflammation
[107]. Moreover, targeting the JAK pathway by administering
tofacitinib (JAK inhibitor) showed lower inflammation due to the
JAK pathway being activated by IL-6 [108].
Th17-targeted therapeutics are not limited to inhibitors and
mABs as microRNAs or miRs have been reported to be vital in the
regulation of Th17 differentiation in periodontitis [109,110]. In
addition, many experiments performed on periodontal ligament
stem cells (PDLCs) have demonstrated the immunomodulatory
potential of these cells. PDLCs maybe assist pro-inflammatory ef-
fects by recruiting leukocytes; also, they secrete IL-1b, IL-6, and sIL-
6R, which may possibly be involved in shifting chemokine pro-
duction, thereby supporting CCR6-expressing cells enrolment in
periodontitis [111,112]. Furthermore, PDLC-stimulated miR-155p-
enriched exosomes explain their immunomodulatory effects on
Th17/Treg ratio [113]. Further studies are needed to deduce the role
and effects of miRs in Th17 differentiation in periodontitis.
Moreover, some studies have highlighted deubiquitylating en-
zymes (DUBs) affect IL-17 signaling via TRAFs, they might be
V. Kini, I. Mohanty, G. Telang et al. Journal of Oral Biosciences 64 (2022) 193e201

Fig. 3. The Th17 mediated pathogenesis in periodontitis and the role of related cytokines and chemokines. (a) Th17 is activated by IL-1b, TGF-b, and IL-21 secreted by Th17 itself
forming a positive feedback loop. (b) IL-17 and IL-22 are secreted by Th17 upon activation. (c) IL-22 binds to fibroblasts, endothelial cells, and epithelial cells which release a salvo of
molecules including RANKL, MMPs, PGE2, CCL2, CXCL1, CXCL2, CXCL8. (d) IL-17 activates B cells and mesenchymal stem cells whereas osteoblasts generate RANKL. (e) The RANKL
binds to osteoclast leading to alveolar bone resorption. (f) The chemokines CCL2, CXCL1, CXCL2, and CXCL8 lead monocyte and dendritic recruitment. (g) The inflammation is
exacerbated as IL-17 is also produced by congenital lymphoid cells, gd T cells, natural killer T cells (NKT), and neutrophils. (h)The M1 polarized macrophage secretes IL-6 and IFN-g
promoting osteoclastic activity. (i) Th17 is also known to release GM-CSF which recruits monocytes and dendritic cells. (j) These recruited monocytes and dendritic cells lead to Th17
differentiation via IL-6 and IL-23.

potential periodontitis modulators. A20, for example, is a DUB-
containing protein that controls Th17 differentiation and IL-17 ac-
tion [114]. A novel approach towards the fabrication of vaccine
against P. gingivalis is also tested by formalin-killed P. gingivalis
injected in mice then infected with live P. gingivalis showed abated
Th17, IL-17A, and lymphocyte proliferation coupled with enhanced
RANKLþ CD4þ T cells, IL-10 and TGF-b1 [115].
Innovative approaches like local biomaterial-mediated delivery
of regulatory molecules like GM-CSF and thymic stromal lympho-
poietin (TSLP) could induce tolerance which may aid in the main-
tenance of periodontal health [116]. This approach may provide an
alternative way of modulating the cytokine setting in inflamed
periodontal tissue. Furthermore, on treatment with low doses (LD),
bone morphogenetic protein-2 (BMP2) and BMP4 micro-
immunotherapy (MI) showed anti-inflammatory and regenerative
properties, which may further ameliorate elevated osteoclastic
activity mediated immune response [117]. Additionally, targeting T
cells directly may also alleviate conditions in periodontitis by
downregulating pro-inflammatory effector functions mediated by
Th17 cells such as Resolvin E1 (RvE1), which is a specialized pro-
resolution mediator (SPMs) and exhibits inhibitory effects on
effector T cells as well as Tregs [118]. Furthermore, metronidazole/
amoxicillin antibiotic treatment given to periodontitis patients
showed reduced IL-1R1 expression on exFoxp3 Th17 cells which
198
further led to reduced IL-1b-stimulated Treg plasticity in patients
and improved periodontitis clinical measures [119].
7. Conclusion
Periodontitis is a complex and multifaceted chronic oral disease
occurring in a sizable population around the world. Periodontitis is
linked to a variety of systemic disorders, including diabetes, obesity,
hypertension, and, particularly, rheumatoid arthritis, according to
data that has progressed from modest to considerable. As a result,
improved and innovative periodontal treatments may lead to better
overall health. Despite the fact that contemporary surgical and
nonsurgical therapies for periodontitis have helped some patients,
the underlying mechanism has yet to be fully established. Many
limitations still exist in the literature regarding the complex
mechanism of this disease and an incomplete understanding of
immune equilibrium disruption in periodontitis.
Because of the concurrent elevation in GM-CSF, the anti-IL-17A
antibody alone did not relieve periodontitis. Would adding an anti-
GM-CSF antibody be beneficial? Furthermore, the variability and
adaptability of Th17 cells have suggested that therapy aimed at
these cells should be revised. Is it possible that ex Th17 cells have
therapeutic potential that we aren't aware of? Is it feasible to
generate a cytokine environment that transforms pathogenic
V. Kini, I. Mohanty, G. Telang et al.
Th17 cells into non-pathogenic Th17 cells? All these are viable
questions, therefore further studies should be aimed at finding
possible solutions to these questions.
Ethical approval
No ethical approval required as no experimentation was
performed.
Author Contribution statement
Dr. Vineet Kini: Contributed in writing original draft of the
manuscript.
Dr. Ipseeta Mohanty: Contributed in the writing original draft
and editing.
Mr. Gaurang Telang: Contributed in literature search and made
all the figures.
Dr. Nishant Vyas: Contributed in study design, review and editing.
Acknowledgment
All figures were created with BioRender.com.
Conflicts of interest
The authors report no conflicts of interest related to this review.
References
[1] Riera Romo M, Pe
rez-Martínez D, Castillo Ferrer C. Innate immunity in ver-
tebrates: an overview. Immunology 2016;148(2):125e39. https://doi.org/
10.1111/imm.12597.
[2] Janeway CA. How the Immune System Works to Protect the Host from
Infection: A Personal View. 2000. www.pnas.orgcgidoi10.1073pnas.131202
998.
[3] Beikler T, Flemmig TF. Oral biofilm-associated diseases: trends and impli-
cations for quality of life, systemic health and expenditures. Periodontol
2000 2011;55(1):87e103. https://doi.org/10.1111/j.1600-0757.2010.00
360.x.
[4] Demmer RT, Papapanou PN. Epidemiologic patterns of chronic and aggres-
sive periodontitis. Periodontol 2000 2010;53(1):28e44. https://doi.org/
10.1111/j.1600-0757.2009.00326.x.
[5] Hajishengallis G, Chavakis T, Lambris JD. Current understanding of peri-
odontal disease pathogenesis and targets for host-modulation therapy.
Periodontol 2000 2020;84(1):14e34. https://doi.org/10.1111/PRD.12331.
[6] Van Dyke TE, Bartold PM, Reynolds EC. The nexus between periodontal
inflammation and dysbiosis. Front Immunol 2020;11. https://doi.org/
10.3389/FIMMU.2020.00511.
[7] Dutzan N, Vernal R, Vaque JP, García-Sesnich J, Hernandez M, Abusleme L,
et al. Interleukin-21 expression and its association with proinflammatory
cytokines in untreated chronic periodontitis patients. J Periodontol
2012;83(7):948e54. https://doi.org/10.1902/jop.2011.110482.
[8] Moutsopoulos NM, Konkel JE. Tissue-specific immunity at the oral mucosal
barrier. Trends Immunol 2018;39(4):276e87. https://doi.org/10.1016/
J.IT.2017.08.005.
[9] Hajishengallis G. The inflammophilic character of the periodontitis-
associated microbiota. Mol Oral Microbiol 2014;29(6):248e57. https://
doi.org/10.1111/OMI.12065.
[10] Naginyte M, Do T, Meade J, Devine DA, Marsh PD. Enrichment of periodontal
pathogens from the biofilms of healthy adults. Sci Rep 2019;9(1). https://
doi.org/10.1038/S41598-019-41882-Y.
[11] Lamont RJ, Hajishengallis G. Polymicrobial synergy and dysbiosis in inflam-
matory disease. Trends Mol Med 2015;21(3):172e83. https://doi.org/
10.1016/J.MOLMED.2014.11.004.
[12] Hajishengallis G, Liang S, Payne MA, Hashim A, Jotwani R, Eskan MA, et al.
Low-abundance biofilm species orchestrates inflammatory periodontal dis-
ease through the commensal microbiota and complement. Cell Host Microbe
2011;10(5):497e506. https://doi.org/10.1016/J.CHOM.2011.10.006.
[13] Shi LX, Zhang L, Zhang DL, Zhou JP, Jiang XJ, Jin YL, et al. Association between
TNF-a G-308A (rs1800629) polymorphism and susceptibility to chronic
periodontitis and type 2 diabetes mellitus: a meta-analysis. J Periodontal Res
2021;56(2):226e35. https://doi.org/10.1111/JRE.12820.
[14] Nascimento GG, Leite FRM, Do LG, Peres KG, Correa MB, Demarco FF, et al. Is
weight gain associated with the incidence of periodontitis? A systematic
review and meta-analysis. J Clin Periodontol 2015;42(6):495e505. https://
doi.org/10.1111/JCPE.12417.
199
Journal of Oral Biosciences 64 (2022) 193e201
[15] Hirota K, Duarte JH, Veldhoen M, Hornsby E, Li Y, Cua DJ, et al. Fate mapping
of IL-17-producing T cells in inflammatory responses. Nat Immunol
2011;12(3):255e63. https://doi.org/10.1038/ni.1993.
[16] Vettore MV, Le~ ao ATT, Monteiro Da Silva AM, Quintanilha RS, Lamarca GA.
The relationship of stress and anxiety with chronic periodontitis. J Clin
Periodontol 2003;30(5):394e402. https://doi.org/10.1034/J.1600-
051X.2003.10271.X.
[17] Mosmann TR, Bond MW, Coffman RL, Ohara J, Paul WE. T-cell and mast cell
lines respond to B-cell stimulatory factor 1. Proc Natl Acad Sci U S A
1986;83(15):5654e8. https://doi.org/10.1073/PNAS.83.15.5654.
[18] Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL, Murphy KM,
et al. Interleukin 17-producing CD4þ effector T cells develop via a lineage
distinct from the T helper type 1 and 2 lineages. Nat Immunol 2005;6(11):
1123e32. https://doi.org/10.1038/ni1254.
[19] Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang YH, et al. A distinct lineage
of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat
Immunol 2005;6(11):1133e41. https://doi.org/10.1038/ni1261.
[20] Yang XO, Pappu BP, Nurieva R, Akimzhanov A, Kang HS, Chung Y, et al. T
helper 17 lineage differentiation is programmed by orphan nuclear receptors
RORa and RORg. Immunity 2008;28(1):29e39. https://doi.org/10.1016/
j.immuni.2007.11.016.
[21] Korn T, Bettelli E, Oukka M, Kuchroo VK. IL-17 and Th17 cells. Annu Rev Immunol
2009;27:485e517. https://doi.org/10.1146/annurev.immunol.021908.132710.
[22] Patel DD, Kuchroo VK. Th17 cell pathway in human immunity: lessons from
genetics and therapeutic interventions. Immunity 2015;43(6):1040e51.
https://doi.org/10.1016/j.immuni.2015.12.003.
[23] Zou W, Restifo NP. TH17 cells in tumour immunity and immunotherapy. Nat
Rev Immunol 2010;10(4):248e56. https://doi.org/10.1038/nri2742.
[24] Sutton CE, Lalor SJ, Sweeney CM, Brereton CF, Lavelle EC, Mills KHG. Inter-
leukin-1 and IL-23 induce innate IL-17 production from gammadelta T cells,
amplifying Th17 responses and autoimmunity. Immunity 2009;31(2):
331e41. https://doi.org/10.1016/J.IMMUNI.2009.08.001.
[25] Passos ST, Silver JS, O'Hara AC, Sehy D, Stumhofer JS, Hunter CA. IL-6 pro-
motes NK cell production of IL-17 during toxoplasmosis. J Immunol
2010;184(4):1776e83. https://doi.org/10.4049/JIMMUNOL.0901843.
[26] Richardson JP, Moyes DL. Adaptive immune responses to Candida albicans
infection. Virulence 2015;6(4):327e37. https://doi.org/10.1080/21505594.
2015.1004977.
[27] McDonald MM, Khoo WH, Ng PY, Xiao Y, Zamerli J, Thatcher P, et al. Oste-
oclasts recycle via osteomorphs during RANKL-stimulated bone resorption.
Cell 2021;184(5):1330e47. https://doi.org/10.1016/J.CELL.2021.02.002. e13.
[28] Dutzan N, Konkel JE, Greenwell-Wild T, Moutsopoulos NM. Characterization
of the human immune cell network at the gingival barrier. Mucosal Immunol
2016;9(5):1163e72. https://doi.org/10.1038/MI.2015.136.
[29] AdibradM,DeyhimiP,GanjalikhaniHakemi M,Behfarnia P,Shahabuei M,RafieeL.
Signsofthe presenceofTh17 cellsin chronic periodontal disease.J Periodontal Res
2012;47(4):525e31. https://doi.org/10.1111/J.1600-0765.2011.01464.X.
[30] Yu JJ, Ruddy MJ, Wong GC, Sfintescu C, Baker PJ, Smith JB, et al. An essential
role for IL-17 in preventing pathogen-initiated bone destruction: recruit-
ment of neutrophils to inflamed bone requires IL-17 receptor-dependent
signals. Blood 2007;109(9):3794e802. https://doi.org/10.1182/BLOOD-2005-
09-010116.
[31] Dutzan N, Kajikawa T, Abusleme L, Greenwell-Wild T, Zuazo CE, Ikeuchi T,
et al. A dysbiotic microbiome triggers T H 17 cells to mediate oral mucosal
immunopathology in mice and humans. Sci Transl Med 2018;10(463).
https://doi.org/10.1126/SCITRANSLMED.AAT0797.
[32] Yu JJ, Ruddy MJ, Conti HR, Boonanantanasarn K, Gaffen SL. The interleukin-17
receptor plays a gender-dependent role in host protection against Por-
phyromonas gingivalis-induced periodontal bone loss. Infect Immun
2008;76(9):4206e13. https://doi.org/10.1128/IAI.01209-07.
[33] Bakır B, Yetkin Ay Z, Büyükbayram HI, _ Kumbul Dog uç D, Bayram D,
Candan IA, et al. Effect of curcumin on systemic T helper 17 cell response;
gingival expressions of interleukin-17 and retinoic acid receptor-related
orphan receptor gt; and alveolar bone loss in experimental periodontitis.
J Periodontol 2016;87(11):e183e91. https://doi.org/10.1902/JOP.2016.
150722.
[34] Milner JD, Brenchley JM, Laurence A, Freeman AF, Hill BJ, Elias KM, et al.
Impaired T(H)17 cell differentiation in subjects with autosomal dominant
hyper-IgE syndrome. Nature 2008;452(7188):773e6. https://doi.org/
10.1038/NATURE06764.
[35] Lee GR. The balance of th17 versus treg cells in autoimmunity. Int J Mol Sci
2018;19(3). https://doi.org/10.3390/ijms19030730.
[36] Nakajima T, Ueki-Maruyama K, Oda T, Ohsawa Y, Ito H, Seymour GJ, et al.
Regulatory T-cells infiltrate periodontal disease tissues. J Dent Res
2005;84(7):639e43. https://doi.org/10.1177/154405910508400711.
[37] Garlet GP, Cardoso CR, Mariano FS, Claudino M, de Assis GF, Campanelli AP,
et al. Regulatory T cells attenuate experimental periodontitis progression in
mice. J Clin Periodontol 2010;37(7):591e600. https://doi.org/10.1111/
J.1600-051X.2010.01586.X.
[38] Tsukasaki M, Komatsu N, Nagashima K, Nitta T, Pluemsakunthai W,
Shukunami C, et al. Host defense against oral microbiota by bone-damaging
T cells. Nat Commun 2018;9(1):1e11. https://doi.org/10.1038/s41467-018-
03147-6. 2018 91.
[39] Kimura A, Kishimoto T. IL-6: regulator of Treg/Th17 balance. Eur J Immunol
2010;40(7):1830e5. https://doi.org/10.1002/EJI.201040391.
V. Kini, I. Mohanty, G. Telang et al.
[40] Xu L, Kitani A, Fuss I, Strober W. Cutting edge: regulatory T cells induce
CD4þCD25-Foxp3- T cells or are self-induced to become Th17 cells in the
absence of exogenous TGF-beta. J Immunol 2007;178(11):6725e9. https://
doi.org/10.4049/JIMMUNOL.178.11.6725.
[41] Korn T, Mitsdoerffer M, Croxford AL, Awasthi A, Dardalhon VA, Galileos G,
et al. IL-6 controls Th17 immunity in vivo by inhibiting the conversion of
conventional T cells into Foxp3þ regulatory T cells. Proc Natl Acad Sci U S A
2008;105(47):18460e5. https://doi.org/10.1073/PNAS.0809850105.
[42] Okui T, Aoki Y, Ito H, Honda T, Yamazaki K. The presence of IL-17þ/FOXP3þ
double-positive cells in periodontitis. J Dent Res 2012;91(6):574e9. https://
doi.org/10.1177/0022034512446341.
[43] Komatsu N, Okamoto K, Sawa S, Nakashima T, Oh-hora M, Kodama T, et al.
Pathogenic conversion of Foxp3þ T cells into TH17 cells in autoimmune
arthritis. Nat Med 2014;20(1):62e8. https://doi.org/10.1038/NM.3432.
[44] Amini A, Pang D, Hackstein CP, Klenerman P. MAIT cells in barrier tissues:
lessons from immediate neighbors. Front Immunol 2020;11. https://doi.org/
10.3389/FIMMU.2020.584521.
[45] Davanian H, Gaiser RA, Silfverberg M, Hugerth LW, Sobkowiak MJ, Lu L, et al.
Mucosal-associated invariant T cells and oral microbiome in persistent apical
periodontitis. Int J Oral Sci 2019;11(2). https://doi.org/10.1038/S41368-019-
0049-Y.
[46] Hall BM. T cells: soldiers and spies-the surveillance and control of effector T
cells by regulatory T cells. Clin J Am Soc Nephrol 2015;10:2050e64. https://
doi.org/10.2215/CJN.06620714.
[47] Yoshimura A, Suzuki M, Sakaguchi R, Hanada T, Yasukawa H, Rubartelli A.
SOCS, inflammation, and autoimmunity. 2012. https://doi.org/10.3389/
fimmu.2012.00020. Published online.
[48] Granet C, Maslinski W, Miossec P. Increased AP-1 and NF-kappaB activation
and recruitment with the combination of the proinflammatory cytokines IL-
1beta, tumor necrosis factor alpha and IL-17 in rheumatoid synoviocytes.
Arthritis Res Ther 2004;6(3). https://doi.org/10.1186/AR1159.
[49] Shen F, Gaffen SL. Structure-function relationships in the IL-17 receptor:
implications for signal transduction and therapy. Cytokine 2008;41(2):
92e104. https://doi.org/10.1016/J.CYTO.2007.11.013.
[50] Dutzan N, Abusleme LT. Helper 17 cells as pathogenic drivers of periodon-
titis. Adv Exp Med Biol 2019;1197:107e17. https://doi.org/10.1007/978-3-
030-28524-1_9.
[51] Veldhoen M. Interleukin 17 is a chief orchestrator of immunity. Nat Immunol
2017;18(6):612e21. https://doi.org/10.1038/NI.3742.
[52] Liu K, Zhao E, Ilyas G, Lalazar G, Lin Y, Haseeb M, et al. Impaired macrophage
autophagy increases the immune response in obese mice by promoting
proinflammatory macrophage polarization. Autophagy 2015;11(2):271e84.
https://doi.org/10.1080/15548627.2015.1009787.
[53] Zhao L, Zhou Y, Xu Y, Sun Y, Li L, Chen W. Effect of non-surgical periodontal
therapy on the levels of Th17/Th1/Th2 cytokines and their transcription
factors in Chinese chronic periodontitis patients. J Clin Periodontol
2011;38(6):509e16. https://doi.org/10.1111/j.1600-051X.2011.01712.x.
[54] Lokhande RV, Ambekar JG, Bhat KG, Dongre NN. Interleukin-21 and its as-
sociation with chronic periodontitis. J Indian Soc Periodontol 2019;23(1):
21e4. https://doi.org/10.4103/jisp.jisp_410_18.
[55] Yang L, Anderson DE, Baecher-Allan C, Hastings WD, Bettelli E, Oukka M,
et al. IL-21 and TGF-beta are required for differentiation of human T(H)17
cells. Nature 2008;454(7202):350e2. https://doi.org/10.1038/NATURE07
021.
[56] Korn T, Bettelli E, Gao W, Awasthi A, Ja€ger A, Strom TB, et al. IL-21 initiates an
alternative pathway to induce proinflammatory T H17 cells. Nature
2007;448(7152):484e7. https://doi.org/10.1038/nature05970.
[57] Wolk K, Kunz S, Witte E, Friedrich M, Asadullah K, Sabat R. IL-22 increases
the innate immunity of tissues. Immunity 2004;21(2):241e54. https://
doi.org/10.1016/J.IMMUNI.2004.07.007.
[58] Díaz-Zún ~ iga J, Melgar-Rodríguez S, Rojas L, Alvarez C, Monasterio G,
Carvajal P, et al. Increased levels of the T-helper 22-associated cytokine
(interleukin-22) and transcription factor (aryl hydrocarbon receptor) in pa-
tients with periodontitis are associated with osteoclast resorptive activity
and severity of the disease. J Periodontal Res 2017;52(5):893e902. https://
doi.org/10.1111/JRE.12461.
[59] Monasterio G, Budini V, Fern
andez B, Castillo F, Rojas C, Alvarez C, et al. IL-
22-expressing CD4 þ AhR þ T lymphocytes are associated with RANKL-
mediated alveolar bone resorption during experimental periodontitis.
J Periodontal Res 2019;54(5):513e24. https://doi.org/10.1111/JRE.12654.
[60] Sonnenberg GF, Nair MG, Kirn TJ, Zaph C, Fouser LA, Artis D. Pathological versus
protective functions of IL-22 in airway inflammation are regulated by IL-17A.
J Exp Med 2010;207(6):1293e305. https://doi.org/10.1084/JEM.20092054.
[61] Eyerich S, Wagener J, Wenzel V, Scarponi C, Pennino D, Albanesi C, et al. IL-22
and TNF-a represent a key cytokine combination for epidermal integrity
during infection with Candida albicans. Eur J Immunol 2011;41(7):
1894e901. https://doi.org/10.1002/EJI.201041197.
[62] Ikeuchi H, Kuroiwa T, Hiramatsu N, Kaneko Y, Hiromura K, Ueki K, et al.
Expression of interleukin-22 in rheumatoid arthritis: potential role as a
proinflammatory cytokine. Arthritis Rheum 2005;52(4):1037e46. https://
doi.org/10.1002/ART.20965.
[63] Kim KW, Kim HR, Park JY, Park JS, Oh HJ, Woo YJ, et al. Interleukin-22 pro-
motes osteoclastogenesis in rheumatoid arthritis through induction of
RANKL in human synovial fibroblasts. Arthritis Rheum 2012;64(4):1015e23.
https://doi.org/10.1002/ART.33446.
200
Journal of Oral Biosciences 64 (2022) 193e201
[64] El-Behi M, Ciric B, Dai H, Yan Y, Cullimore M, Safavi F, et al. The encephali-
togenicity of T(H)17 cells is dependent on IL-1- and IL-23-induced produc-
tion of the cytokine GM-CSF. Nat Immunol 2011;12(6):568e75. https://
doi.org/10.1038/NI.2031.
[65] Aschenbrenner D, Foglierini M, Jarrossay D, Hu D, Weiner HL, Kuchroo VK,
et al. An immunoregulatory and tissue-residency program modulated by c-
MAF in human T H 17 cells. Nat Immunol 2018;19(10):1126e36. https://
doi.org/10.1038/S41590-018-0200-5.
[66] Mazzoni A, Maggi L, Liotta F, Cosmi L, Annunziato F. Biological and clinical
significance of T helper 17 cell plasticity. Immunology 2019;158(4):287e95.
https://doi.org/10.1111/IMM.13124.
[67] Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, et al. Reciprocal
developmental pathways for the generation of pathogenic effector TH17 and
regulatory T cells. Nature 2006;441(7090):235e8. https://doi.org/10.1038/
nature04753.
[68] Coquet JM, Chakravarti S, Smyth MJ, Godfrey DI. Cutting edge: IL-21 is not
essential for Th17 differentiation or experimental autoimmune encephalo-
myelitis. J Immunol 2008;180(11):7097e101. https://doi.org/10.4049/
jimmunol.180.11.7097.
[69] Sonderegger I, Kisielow J, Meier R, King C, Kopf M. IL-21 and IL-21R are not
required for development of Th17 cells and autoimmunity in vivo. Eur J
Immunol 2008;38(7):1833e8. https://doi.org/10.1002/eji.200838511.
[70] Zenewicz LA, Yancopoulos GD, Valenzuela DM, Murphy AJ, Stevens S,
Flavell RA. Innate and adaptive interleukin-22 protects mice from inflam-
matory bowel disease. Immunity 2008;29(6):947e57. https://doi.org/
10.1016/j.immuni.2008.11.003.
[71] Ogawa A, Andoh A, Araki Y, Bamba T, Fujiyama Y. Neutralization of
interleukin-17 aggravates dextran sulfate sodium-induced colitis in mice.
Clin Immunol 2004;110(1):55e62. https://doi.org/10.1016/j.clim.2003.
09.013.
[72] O’Connor W, Kamanaka M, Booth CJ, Town T, Nakae S, Iwakura Y, et al. A
protective function for interleukin 17A in T cell-mediated intestinal
inflammation. Nat Immunol 2009;10(6):603e9. https://doi.org/10.1038/
ni.1736.
[73] Dankers W, Davelaar N, Van Hamburg JP, Van De Peppel J, Colin EM,
Lubberts E. Human memory Th17 cell populations change into anti-
inflammatory cells with regulatory capacity upon exposure to active
Vitamin D. Front Immunol 2019;10(JULY). https://doi.org/10.3389/
fimmu.2019.01504.
[74] McGeachy MJ, Bak-Jensen KS, Chen Y, Tato CM, Blumenschein W,
McClanahan T, et al. TGF-b and IL-6 drive the production of IL-17 and IL-10
by T cells and restrain TH-17 cell-mediated pathology. Nat Immunol
2007;8(12):1390e7. https://doi.org/10.1038/ni1539.
[75] Stumhofer JS, Silver JS, Laurence A, Porrett PM, Harris TH, Turka LA, et al.
Interleukins 27 and 6 induce STAT3-mediated T cell production of inter-
leukin 10. Nat Immunol 2007;8(12):1363e71. https://doi.org/10.1038/
ni1537.
[76] Wang C, Yosef N, Gaublomme J, Wu C, Lee Y, Clish CB, et al. CD5L/AIM
regulates lipid biosynthesis and restrains Th17 cell pathogenicity. Cell
2015;163(6):1413e27. https://doi.org/10.1016/j.cell.2015.10.068.
[77] Wang Y, Godec J, Ben-Aissa K, Cui K, Zhao K, Pucsek AB, et al. The tran-
scription factors T-bet and Runx are required for the ontogeny of pathogenic
interferon-g-producing T helper 17 cells. Immunity 2014;40(3):355e66.
https://doi.org/10.1016/J.IMMUNI.2014.01.002.
[78] Hirota K, Duarte JH, Veldhoen M, Hornsby E, Li Y, Cua DJ, et al. Fate mapping
of IL-17-producing T cells in inflammatory responses. Nat Immunol
2011;12(3):255e63. https://doi.org/10.1038/NI.1993.
[79] Cerboni S, Gehrmann U, Preite S, Mitra S. Cytokine-regulated Th17 plasticity
in human health and diseases. Immunology 2021;163(1):3e18. https://
doi.org/10.1111/IMM.13280.
[80] Maggi L, Santarlasci V, Capone M, Rossi MC, Querci V, Mazzoni A, et al.
Distinctive features of classic and nonclassic (Th17 derived) human Th1
cells. Eur J Immunol 2012;42(12):3180e8. https://doi.org/10.1002/EJI.2012
42648.
[81] Bittner-Eddy PD, Fischer LA, Costalonga M. Transient expression of IL-17a in
Foxp3 fate-tracked cells in porphyromonas gingivalis-mediated oral dys-
biosis. Front Immunol 2020;11. https://doi.org/10.3389/fimmu.2020.00677.
[82] Landzberg M, Doering H, Aboodi GM, Tenenbaum HC, Glogauer M. Quanti-
fying oral inflammatory load: oral neutrophil counts in periodontal health
and disease. J Periodontal Res 2015;50(3):330e6. https://doi.org/10.1111/
JRE.12211.
[83] Maekawa T, Krauss JL, Abe T, Jotwani R, Triantafilou M, Triantafilou K, et al.
Porphyromonas gingivalis manipulates complement and TLR signaling to
uncouple bacterial clearance from inflammation and promote dysbiosis. Cell
Host Microbe 2014;15(6):768e78. https://doi.org/10.1016/J.CHOM.2014.
05.012.
[84] Nussbaum G, Shapira L. How has neutrophil research improved our under-
standing of periodontal pathogenesis? J Clin Periodontol 2011;38(Suppl 11):
49e59. https://doi.org/10.1111/J.1600-051X.2010.01678.X (SUPPL. 11).
[85] Scapini P, Cassatella MA. Social networking of human neutrophils within the
immune system. Blood 2014;124(5):710e9. https://doi.org/10.1182/BLOOD-
2014-03-453217.
[86] Pelletier M, Maggi L, Micheletti A, Lazzeri E, Tamassia N, Costantini C, et al.
Evidence for a cross-talk between human neutrophils and Th17 cells. Blood
2010;115(2):335e43. https://doi.org/10.1182/BLOOD-2009-04-216085.
V. Kini, I. Mohanty, G. Telang et al.
[87] Zenobia C, Hajishengallis G. Basic biology and role of interleukin-17 in im-
munity and inflammation. Periodontol 2000 2015;69(1):142e59. https://
doi.org/10.1111/PRD.12083.
[88] Zenobia C, Hajishengallis G. Basic biology and role of interleukin-17 in im-
munity and inflammation. Periodontol 2000 2015;69(1):142e59. https://
doi.org/10.1111/prd.12083.
[89] Cheng WC, van Asten SD, Burns LA, Evans HG, Walter GJ, Hashim A, et al.
Periodontitis-associated pathogens P. gingivalis and A. actino-
mycetemcomitans activate human CD14(þ) monocytes leading to enhanced
Th17/IL-17 responses. Eur J Immunol 2016;46(9):2211e21. https://doi.org/
10.1002/EJI.201545871.
[90] Nares S, Moutsopoulos NM, Angelov N, Rangel ZG, Munson PJ, Sinha N, et al.
Rapid myeloid cell transcriptional and proteomic responses to perio-
dontopathogenic Porphyromonas gingivalis. Am J Pathol 2009;174(4):
1400e14. https://doi.org/10.2353/AJPATH.2009.080677.
[91] Cheng WC, van Asten SD, Burns LA, Evans HG, Walter GJ, Hashim A, et al.
Periodontitis-associated pathogens P. gingivalis and A. actino-
mycetemcomitans activate human CD14þ monocytes leading to enhanced
Th17/IL-17 responses. Eur J Immunol 2016;46(9):2211e21. https://doi.org/
10.1002/eji.201545871.
[92] Zhang C, Xu C, Gao L, Li X, Zhao C. Porphyromonas gingivalis lipopolysac-
charide promotes T-hel per17 cell differentiation by upregulating Delta-like
ligand 4 expression on CD14 þ monocytes. PeerJ 2021;9. https://doi.org/
10.7717/PEERJ.11094.
[93] Alvarez C, Benítez A, Rojas L, Pujol M, Carvajal P, Díaz-Zún ~ iga J, et al. Dif-
ferential expression of CC chemokines (CCLs) and receptors (CCRs) by human
T lymphocytes in response to different Aggregatibacter actino-
mycetemcomitans serotypes. J Appl Oral Sci 2015;23(6):580e90. https://
doi.org/10.1590/1678-775720150285.
[94] Van Raemdonck K, Umar S, Palasiewicz K, Volkov S, Volin MV, Arami S, et al.
CCL21/CCR7 signaling in macrophages promotes joint inflammation and
Th17-mediated osteoclast formation in rheumatoid arthritis. Cell Mol Life Sci
2020;77(7):1387e99. https://doi.org/10.1007/S00018-019-03235-W.
[95] Hajishengallis G. Immunomicrobial pathogenesis of periodontitis: keystones,
pathobionts, and host response. Trends Immunol 2014;35(1):3e11. https://
doi.org/10.1016/J.IT.2013.09.001.
[96] Moutsopoulos NM, Kling HM, Angelov N, Jin W, Palmer RJ, Nares S, et al.
Porphyromonas gingivalis promotes Th17 inducing pathways in chronic
periodontitis. J Autoimmun 2012;39(4):294e303. https://doi.org/10.1016/
J.JAUT.2012.03.003.
[97] Chopra A, Bhat SG, Sivaraman K. Porphyromonas gingivalis adopts intricate
and unique molecular mechanisms to survive and persist within the host: a
critical update. J Oral Microbiol 2020;12(1). https://doi.org/10.1080/
20002297.2020.1801090.
[98] Zhang L, Gao L, Xu C, Li X, Wang P, Zhang C, et al. Porphyromonas gingivalis
lipopolysaccharide promotes T- helper 17 cell differentiation from human
CD4 þ naïve T cells via toll-like receptor-2 in vitro. Arch Oral Biol 2019;107.
https://doi.org/10.1016/J.ARCHORALBIO.2019.104483.
[99] Dutzan N, Kajikawa T, Abusleme L, Greenwell-Wild T, Zuazo CE, Ikeuchi T,
et al. A dysbiotic microbiome triggers T H 17 cells to mediate oral mucosal
immunopathology in mice and humans. Sci Transl Med 2018;10(463).
https://doi.org/10.1126/SCITRANSLMED.AAT0797.
[100] Zwicky P, Unger S, Becher B. Targeting interleukin-17 in chronic inflam-
matory disease: a clinical perspective. J Exp Med 2020;217(1). https://
doi.org/10.1084/JEM.20191123.
[101] Papp KA, Reich K, Paul C, Blauvelt A, Baran W, Bolduc C, et al. A prospective
phase III, randomized, double-blind, placebo-controlled study of brodalumab
in patients with moderate-to-severe plaque psoriasis. Br J Dermatol
2016;175(2):273e86. https://doi.org/10.1111/BJD.14493.
[102] Yu JJ, Ruddy MJ, Wong GC, Sfintescu C, Baker PJ, Smith JB, et al. An essential
role for IL-17 in preventing pathogen-initiated bone destruction: recruit-
ment of neutrophils to inflamed bone requires IL-17 receptor-dependent
signals. Blood 2007;109(9):3794e802. https://doi.org/10.1182/BLOOD-
2005-09-010116.
[103] Zhou L. Ivanov II, Spolski R, et al. IL-6 programs T(H)-17 cell differentiation
by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat
Immunol 2007;8(9):967e74. https://doi.org/10.1038/NI1488.
201
Journal of Oral Biosciences 64 (2022) 193e201
[104] Nishimoto N, Terao K, Mima T, Nakahara H, Takagi N, Kakehi T. Mechanisms
and pathologic significances in increase in serum interleukin-6 (IL-6) and
soluble IL-6 receptor after administration of an anti-IL-6 receptor antibody,
tocilizumab, in patients with rheumatoid arthritis and Castleman disease.
Blood 2008;112(10):3959e64. https://doi.org/10.1182/BLOOD-2008-05-
155846.
[105] Kobayashi T, Okada M, Ito S, Kobayashi D, Ishida K, Kojima A, et al. Assess-
ment of interleukin-6 receptor inhibition therapy on periodontal condition
in patients with rheumatoid arthritis and chronic periodontitis. J Periodontol
2014;85(1):57e67. https://doi.org/10.1902/JOP.2013.120696.
[106] Ancuța C, Chirieac R, Ancuța E, Ț anculescu O, Solomon SM, Fa tu AM, et al.
Exploring the role of interleukin-6 receptor inhibitor tocilizumab in patients
with active rheumatoid arthritis and periodontal disease. J Clin Med
2021;10(4):1e12. https://doi.org/10.3390/JCM10040878.
[107] Moutsopoulos NM, Zerbe CS, Wild T, Dutzan N, Brenchley L, DiPasquale G,
et al. Interleukin-12 and interleukin-23 blockade in leukocyte adhesion
deficiency type 1. N Engl J Med 2017;376(12):1141e6. https://doi.org/
10.1056/NEJMOA1612197.
[108] Kobayashi T, Ito S, Murasawa A, Ishikawa H, Yoshie H. Effects of tofacitinib on
the clinical features of periodontitis in patients with rheumatoid arthritis:
two case reports. BMC Rheumatol 2019;3(1). https://doi.org/10.1186/
S41927-019-0062-Y.
[109] Kagiya T. MicroRNAs: potential biomarkers and therapeutic targets for
alveolar bone loss in periodontal disease. Int J Mol Sci 2016;17(8). https://
doi.org/10.3390/IJMS17081317.
[110] Yuan Y, Zhang H, Huang H. microRNAs in inflammatory alveolar bone defect:
a review. J Periodontal Res 2021;56(2):219e25. https://doi.org/10.1111/
JRE.12819.
[111] Konermann A, Beyer M, Deschner J, Allam JP, Novak N, Winter J, et al. Human
periodontal ligament cells facilitate leukocyte recruitment and are influ-
enced in their immunomodulatory function by Th17 cytokine release. Cell
Immunol 2012;272(2):137e43. https://doi.org/10.1016/j.cellimm.2011.
10.020.
[112] Hosokawa Y, Shindo S, Hosokawa I, Ozaki K, Matsuo T. IL-6 trans-signaling
enhances CCL20 production from IL-1b-stimulated human periodontal lig-
ament cells. Inflammation 2014;37(2):381e6. https://doi.org/10.1007/
s10753-013-9750-8.
[113] Zheng Y, Dong C, Yang J, Jin Y, Zheng W, Zhou Q, et al. Exosomal microRNA-
155-5p from PDLSCs regulated Th17/Treg balance by targeting sirtuin-1 in
chronic periodontitis. J Cell Physiol 2019;234(11):20662e74. https://doi.org/
10.1002/jcp.28671.
[114] Garg AV, Ahmed M, Vallejo AN, Ma A, Gaffen SL. The deubiquitinase A20
mediates feedback inhibition of interleukin-17 receptor signaling. Sci Signal
2013;6(278). https://doi.org/10.1126/SCISIGNAL.2003699.
[115] Wang L, Guan N, Jin Y, Lin X, Gao H. Subcutaneous vaccination with Por-
phyromonas gingivalis ameliorates periodontitis by modulating Th17/Treg
imbalance in a murine model. Int Immunopharm 2015;25(1):65e73. https://
doi.org/10.1016/j.intimp.2015.01.007.
[116] Sands RW, Verbeke CS, Ouhara K, Silva EA, Hsiong S, Kawai T, et al.
Tuning cytokines enriches dendritic cells and regulatory T cells in the
periodontium. J Periodontol 2020;91(11):1475e85. https://doi.org/10.
1002/JPER.19-0411.
[117] Ferra-Can
~ ellas M del M, Munar-Bestard M, Garcia-Sureda L, Lejeune B,
Ramis JM, Monjo M. BMP4 micro-immunotherapy increases collagen
deposition and reduces PGE2 release in human gingival fibroblasts and
increases tissue viability of engineered 3D gingiva under inflammatory
conditions. J Periodontol 2021. https://doi.org/10.1002/JPER.20-0552. Pub-
lished online.
[118] Alvarez C, Abdalla H, Sulliman S, Rojas P, Wu YC, Almarhoumi R, et al. RvE1
impacts the gingival inflammatory infiltrate by inhibiting the T cell response
in experimental periodontitis. Front. Immunol. 2021;12:1. https://doi.org/
10.3389/fimmu.2021.664756. Article.
[119] Rajendran M, Looney S, Singh N, Elashiry M, Meghil MM, El-Awady AR, et al.
Systemic antibiotic therapy reduces circulating inflammatory dendritic cells
and tregeTh17 plasticity in periodontitis. J Immunol 2019;202(9):2690e9.
https://doi.org/10.4049/JIMMUNOL.1900046/-/DCSUPPLEMENTAL.