|

Received: 19 January 2018    Accepted: 21 April 2018

DOI: 10.1111/cpr.12475

REVIEW

Critical role of inflammatory mast cell in fibrosis: Potential

therapeutic effect of IL-­37

P. Conti1  | Al. Caraffa2 | F. Mastrangelo3 | L. Tettamanti4 | G. Ronconi5 | 

I. Frydas6 | S. K. Kritas7 | T. C. Theoharides8

1
Postgraduate Medical School, University of
Chieti, Chieti, Italy Abstract
2
Department of Pharmacy, University of Background: Fibrosis involves the activation of inflammatory cells, leading to a de-
Perugia, Perugia, Italy
crease in physiological function of the affected organ or tissue.
3
Department of Medical Science and
Aims: To update and synthesize relevant information concerning fibrosis into a new
Biotechnology, University of Foggia, Foggia,
Italy hypothesis to explain the pathogenesis of fibrosis and propose potential novel thera-
4
Department of Medical and Morphological peutic approaches.
Science, University of Insubria, Varese, Italy
5
Materials and Methods: Literature was reviewed and relevant information is dis-
UOS Clinica dei Pazienti del
Territorio, Policlinico Gemelli, Rome, Italy cussed in the context of the pathogenesis of fibrosis.
6
Faculty of Parasitology, Aristotle University Results: A number of cytokines and their mRNA are involved in the circulatory sys-
of Thessaloniki, Macedonia, Greece
tem and in organs of patients with fibrotic tissues. The profibrotic cytokines are gen-
7
Department of Microbiology, University of
Thessaloniki, Thessaloniki, Greece
erated by several activated immune cells, including fibroblasts and mast cells (MCs),
8
Department of Integrative Physiology which are important for tissue inflammatory responses to different types of injury.
and Pathobiology, Molecular MC-­derived TNF, IL-­1, and IL-­33 contribute crucially to the initiation of a cascade of
Immunopharmacology and Drug Discovery
Laboratory, Tufts University School of the host defence mechanism(s), leading to the fibrosis process. Inhibition of TNF and
Medicine, Boston, MA, USA inflammatory cytokines may slow the progression of fibrosis and improve the patho-
Correspondence logical status of the affected subject. IL-­37 is generated by various types of immune
Pio Conti, Postgraduate Medical School, cells and is an IL-­1 family member protein. IL-­37 is not a receptor antagonist; it binds
University of Chieti-Pescara, Chieti, Italy.
Email: pconti@unich.it IL-­18 receptor alpha (IL-­18Rα) and delivers the inhibitory signal by using TIR8. It has
been shown that IL-­37 can be protective in inflammation and injury, and inhibits both
innate and adaptive immunity.
Discussion: IL-­37 may be useful for suppression of inflammatory diseases induced by
inhibiting MyD88-­dependent TLR signalling. In addition, IL-­37 downregulates NF-­κB
induced by TLR2 or TLR4 through a mechanism dependent on IL-­18Rα.
Conclusion: This review summarizes current knowledge on the role of MC in inflam-
mation and tissue/organ fibrosis, with a focus on the therapeutic potential of IL-­37-­
targeting cytokines.

1 |  I NTRO D U C TI O N including inflammatory cytokines, such as IL-­1, which is generated

by infiltrated and resident immune cells in inflamed tissue. In fact, in
Tissue damage and inflammation can be caused by different acute 1986, we reported that IL-­1 represents a family of polypeptides with
and chronic stimuli, chemical, physical and/or biological. Among the a wide range of biological activities and plays an important role in the
biological damages that cause tissue dysregulation are: ischaemia, pathogenesis of various infectious and inflammatory, neoplastic and
autoimmune diseases, infections and toxic biological substances immunological disorders.1,2

Cell Proliferation. 2018;51:e12475. wileyonlinelibrary.com/journal/cpr © 2018 John Wiley & Sons Ltd  |  1 of 8
https://doi.org/10.1111/cpr.12475
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Fibrosis is a dysregulation in collagen synthesis, with increased production of IL-­13 and TGF-­β, promoting fibroblast proliferation
deposition of collagens, (primarily types I and III), and other extra- and fibrinogenesis.9
cellular matrix proteins in a number of organs, with the involvement In chronic damage, CD4+ lymphocytes activate and produce cy-
of inflammatory cytokines, and dysfunction of the microvasculature tokines that stimulate macrophages and other inflammatory cells
and immunological parameters with a mechanism that is thought to characteristic of the chronic reaction. The latter also produce cyto-
3
be an overactive wound healing process. kines that stimulate the lymphocytes, thus establishing an adaptive
Fibrosis can affect nearly all tissues and organ systems, but often immune response and an inflammatory circuit.10
is most present in: inflammatory vessels, skin disease, interstitial Degradation or necrosis products can be associated with “danger-­
lung disease, liver cirrhosis, kidney disease, heart disease, diseases associated molecular patterns” or DAMPs that have receptors called
of the eye, atherosclerosis and scleroderma.4 “pattern recognition receptors” (PRRs). These receptors also include
In fibrosis, the reparative process is characterized by a connec- toll-­like receptors (TLRs) which play a crucial role in innate and adap-
tive tissue that replaces normal parenchymal tissue and sometimes tive immunity, and the activation of TLR2, TLR3 or TLR4 upregulates
can cause morbidity. Approximately 45% mortality in the Western the production of inflammatory mediators in human diseases. The
5
world is due to this disease. Fibrosis begins as a healing process adaptive immune responses are regulated by STAT4, which is a major
but can subsequently be pathogenic as it remodels the tissue with transcription factor that can be also detrimental in several immune
a badly functioning scarring process.6 However, the exact mech- disorders.11
anisms that cause tissue/organ fibrosis remain not completely Stimulation of TLR4 increases the production of intercellular ad-
understood. hesion molecule-­1, monocyte chemoattractant protein-­1 (MCP-­1)
The affected organ normally presents an inflammatory state me- and inflammatory cytokines. Knockdown of myeloid differentiation
diated by immune cells such as macrophages, lymphocytes CD4+, factor 88 (MyD88) affects inflammatory mediator production fol-
eosinophils, plasma cells, CD8+ T cells, fibroblasts and mast cells lowing TLR4 stimulation.12
(MCs).7 These cells, once activated, generate inflammatory prod- Organ/tissue fibrosis is also mediated by the cytokines TGF-­β1
ucts including proteolytic enzymes, growth factors and cytokines, and 2, which are the major proteins involved in this disease.13
which participate in the formation of connective tissue destroying Thus, fibrinogenesis is correlated with the CD4+ lymphocytes
7
the physiological one. Increased proteins and mRNAs for multiple which, once activated, produce cytokines such as, IL-­4, IL-­5, IL-­13
profibrotic cytokines and chemokines have been revealed in several and IFNγ.14 The activation of TH1 cells generates cytokines that
8
tissues/organs and the circulatory system. activate Th2 cells to produce IL-­13 (the major profibrotic mediator)
Type 2 immunity is mediated by MCs, eosinophils, basophils and which causes the synthesis of collagen with fibrosis formation and
T helper 2 cells, and by cytokines IL-­4, IL-­5, IL-­9, IL-­13, IL-­25 and IL-­ extracellular matrix remodelling as part of an attempted reparative
33, while that of type 1 is characterized by macrophages, mast cells process after injury.15
7
and neutrophils. Recently, it has been seen that these two immu- Type 1 or type 2 immunity may be protective or may play a
nities work and collaborate in a crossover way.9 In fibrosis, there is pathogenic role. Type 2 immunity with IL-­4 and IL-­13 production is
initially a rapid inflammatory response due to TH1 cytokines and directly involved in the regeneration and repair of tissues damaged
subsequently a TH2 immune response which is established with by environmental insults.14,15

F I G U R E   1   Mast cell-­mediated tissue

fibrosis. This figure depicts a tissue which
releases TGF-­β, activating monocyte
which participate in angiogenesis and
fibrosis. In addition, activated mast cells
release chemical mediators, TGF-­β and
angiotensin II, which also participate in
fibrotic processes
CONTI et al. |
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During the inflammatory response and neovascularization, MCs, histamine, tryptase and chymase, are elevated in tissue and organs
as well as monocyte/macrophages, are important for their expres- affected by fibrosis. 28 This number increases along with the aug-
sion of fibroblast growth factor (FGF) at both mRNA and protein lev- mentation of the number of fibroblasts and their infiltration, tightly
els, which contribute to cell proliferation, fibrosis and angiogenesis16 attached to fibroblasts, is associated with the degree of fibrosis
(Figure 1). which can occur in various diseases. 29,30
Fibroblasts are also fundamental cells of the connective tis- In fact, asthmatic patients may present fibrotic events with ac-
sue, located in every tissue and organ and produce numerous tivation of fibroblasts due to the interaction with MCs that can re-
substances such as fibronectin, proteoglycans, collagen and cyto- lease various growth factors (TGF-­β, SCF, NGF, VEGF, FGF) which
kines. Fibroblasts remodel extracellular molecules (ECM) by col- participate in wound healing and promote cell growth of keratino-
laborating with IL-­13 lymphocytes, monocytes and MC products. cytes and collagen.31
These cells express different receptors including PDGF(R) and In cirrhosis of the liver, fibrosis is characterized by accumulation
5-­lipoxygenase(R) which produces chemoattractant and inflamma- of extracellular matrix rich in collagen I and III, accompanied by liver
tory leukotrienes.17 failure, hypertension and risk of neoplastic formation.32
Mast cells participate in the fibrosis process by producing TGF-­β In experimental models of fibrosis in rodents, it has been reported
(which induces fibroblast proliferation and migration), IL-­
33, IL-­
1 that MCs can release renin with generation of angiotensin which is
mRNA, IL-­18 and other inflammatory cytokines, and also collagen. degraded by MC chymase, leading to the formation of angiotensin II
and then to the fibrosis process. In addition, the histamine released
by the MCs also activates the fibroblasts by participating in tissue
2 | M A S T C E LL S fibrosis.31
In turn, fibroblasts influence the development and activation
Mast cells are of haematopoietic origin, characterized by prominent of MCs and their FcεRI receptor, releasing IL-­3 and SCF which act
cytoplasmic granules, and derive from CD34+ haematopoietic stem by binding to the tyrosine kinase receptor c-­Kit (CD117), expressed
cells.18 MCs are derived from circulating progenitors which migrate by both precursors and mature MCs.33 In addition, the products
to tissues where they finally differentiate, mature and reside virtu- released by activated fibroblast allow the survival of MCs and also
ally in all vascularized tissues.18 They are abundant in the skin, in cause the release of histamine and the chemokine eotaxin genera-
close proximity to blood vessels, lymphatics, nerves, secretory tion, which chemoattracts immune cells.31
glands and mucosal body surfaces where, along with other immune From these observations, we can surely deduce that MCs and
cells, such as dendritic cells (DCs), macrophages, fibroblasts and lym- fibroblast cross-­
t alk influence each other in fibrotic diseases.
phocytes, they play a role of “sentinels” against the environmental Therefore, MCs play an important role in tissue remodelling and
19,20
challenges. fibrosis.
Among the many receptors expressed by MCs, there is the im-
portant receptor for IgE, the FcεRI which when activated releases
important chemical and lipid mediators of de novo synthesis and cy- 3 | M AC RO PH AG E S
21
tokines and chemokines induced by “alarmins”.
“Alarmins” are factors induced by DAMPs and released from Activated macrophages are crucial in the pathogenesis of fibrosis,
damaged cells. They have the ability to immediately recruit innate since they carry out phagocitic activity on tissue debris and dead
immune inflammatory cells such as monocytes/macrophages, den- cells. They also release cytokines/chemokines which recruit and ac-
22
dritic cells and MCs. DAMPs are involved in inflammation by bind- tivate the profibrotic Th2 cell-­derived IL-­13.7 In local milieu, mac-
ing the receptor of chemokines on immune cells. rophages are influenced by several factors and undergo phenotypic
Mast cells mediate innate and adaptive immunity, and cause in- and metabolic changes, directly influencing the fibrogenesis process
flammation and tissue remodelling collaborating in fibrous tissues through the secretion of matrix metalloproteinase (MMP) and other
23
with fibroblasts. factors.
Innate immunity mediated by TLRs leads to the generation of Activation of macrophages secretes IL-­4 and IL-­13 which also
inflammatory cytokines including IL-­
1, IL-­
18, IL-­
33, IL-­
36 among provokes the release of MMP which may result in an increase in
others. 24 fibrotic activity. The inhibition of TNF and other proinflammatory
In tissue damage, increased IL-­1, IL-­33 and IL-­18 levels are di- cytokines/chemokines generated by macrophages may prevent
rectly correlated with increased acute inflammation modulated via fibrinogenesis.7
25
TLR4 signalling. In fibrosis, TGF-­β, along with IL-­10, is released by macrophages
In chronic allergic disorders and MC studies in vitro, there is which promote the differentiation of Treg cells, modulating dendritic
an involvement of mediation, development and activation of fibro- cells and Th2 cells. In addition, activated fibroblasts generate imma-
blasts. 26 MCs that physiologically perform a protective beneficial ture TGF-­β which, through the integrin receptors and other factors,
function can also contribute to the fibrotic process and tissue dys- provokes the release of mature TGF-­β, a crucial factor for the patho-
function and damage. 27 MC numbers and their mediators, such as genic profibrotic activity and tissue repair.7
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4 of 8       CONTI et al.

4 |   I L-­1 cytotoxicity, angiogenesis and it is involved in thickening of the

airway walls.
Inflammasome activation, which regulates the release of IL-­1, IL-­ TNF is generated by its precursor transmembrane TNF (26 kDa),
18 and IL-­3 3, together with IL-­17A is a central driver of fibrosis which is cleaved by a converting enzyme in mature TNF (17 kDa) bi-
and can mediate this process with the involvement of TGF-­β and ologically active soluble form.46
the rise of cytokines IL-­4 and IL-­13. 34,35 Inflammasome and inflam- TNF has been linked to a number of diseases including interstitial
matory IL-­1 family members can act synergistically in the fibrotic tissue fibrosis and acute and chronic inflammation.43,47 In addition,
process. TNF upregulates the expression of adhesion molecules, and inflam-
IL-­1 family members consist of seven agonists, IL-­1α, IL-­1β, IL-­18, matory cytokines and increases the generation of MMP-­1, promoting
IL-­33, IL-­36α, IL-­36β and IL-­36γ, three antagonists, IL-­1Ra, IL-­36Ra tissue damage, and remodelling via NFκB transcription activation.48
and IL-­38, and one anti-­inflammatory cytokine IL-­37. Inhibition of Tissue fibrosis is characterized by a decline in organ function
IL-­1 can attenuate inflammation and fibrosis by inhibiting other in- with increased levels of TNF, suggesting a key role of this cytokine
flammatory and fibrogenic mediators.36,37 in fibrinogenesis.
IL-­1 is involved in the promotion of collagen synthesis and in the Lack of TNFRI, II and III receptors, can have a protective effect
increase in expression of transforming growth factor (TGF-­β), which and attenuate histopathological alterations in organ fibrosis.49
is an important profibrotic growth factor in fibrinogenesis.38,39 Inhibiting MC-­derived TNF and histamine, which may contribute
Cytokines, including TGF-­β, may stimulate fibroblast proliferation to fibrin formation by increasing vascular permeability and downregu-
and collagen deposition which are important in tissue remodelling. lating cytokine/chemokine generation, may have a therapeutic effect,
Furthermore, TNF, IL-­1 and IL-­33 also augment fibroblast prolifer- demonstrating an important role of TNF and other cytokines in fibrin-
ation and collagen synthesis leading to tissue fibrosis.38 In addition, ogenesis induced in the organism by external environmental insults.50
TGF-­β, which is increased by angiotensin II, inhibits matrix metallo- The administration of anti-­inflammatory cytokines or anti-­mast
40
proteinase (MMP-­1)-­induced degradation of collagen. cell chemical mediators may have an anti-­fibrotic therapeutic effect,
Mast cells secrete high levels of TGF-­β, TNF and IL-­6, and low by restoring the functionality of the tissues and/or organs.51
levels of IL-­1; on the other hand, they can be activated with several Therefore, the inhibition of inflammatory IL-­1 family members
cytokines including IL-­6, SCF, TNF, IL-­33 and IL-­1.41 could ameliorate a number of inflammatory diseases including tissue
The profibrotic cytokines, such as IL-­1, TNF, IL-­33 and others, fibrosis.
increase fibroblast proliferation leading to greater collagen synthesis
and then fibrosis.4
Inflammatory IL-­1 family members play an important role in the 6 | I L-­3 3/S T 2 A N D FI B ROS I S
innate response to infections and in acute and chronic inflammation
and are profibrotic cytokines. The abnormal expression of IL-­1 that IL-­33 is located in humans on chromosome 9, and the size of full-­
promotes fibroblast proliferation, and the generation of IL-­33 can length protein is about 30 kDa, which translocates to the nucleus
contribute to fibrosis, whereas IL-­6 stimulated by IL-­1 and PDGFα where it has intracrine gene regulatory functions.52
could be involved in procollagen type I production. IL-­33 also in- IL-­33 is produced by epithelial cells, fibroblasts, endothelial cells,
creases collagen VI, III and MMP-­1.42 macrophages, mast cells and others. It responds to microbial, allergic
Mast cells not only produce TNF at the transcriptional and trans- and inflammatory stimuli, even if it is not clear how it is secreted
lational level, but are the only known cells able to prestore TNF in by the cells. This inflammatory cytokine has also been defined as
43
their granules, which can be released in seconds after activation. an “alarmin” signal in response to external stimulus. The IL-­33 full-­
length protein is split by caspase-­1 into mature forms that bind to
its ST2 receptor, previously known as an orphan receptor of the IL-­1
5 | TN F A N D FI B ROS I S receptor family, and activates MyD88.
IL-­33 is mainly an important initiator and maintainer of type
The exposure of the organism to the pathological damaging in- 2-­associated mucosal inflammation and immunity.53
sults can induce a pathological response with acute inflammation IL-­33 exerts its biological effects on many tissues and cells, in-
of the organ and accumulation of inflammatory cells, including cluding MCs, and plays an important role in adaptive immunity and
MCs, with TNF release.44 It is well known that TNF is linked to a allergy. It is important in the physiological remodelling of tissues, in
number of inflammatory diseases inducing recruitment of immune cell hyperplasia and in the production of other cytokines such as IL-­5
cells, inflammation, hyper-­responsiveness and tissue remodelling. and IL-­13. In addition, IL-­33 stimulates the production of IL-­6, TNF
TNF generated by macrophages and MCs, along with proinflam- and IL-­1 in APC cells, while on TH2 lymphocytes it stimulates the
matory IL-­1 family members are the crucial modulators of inflam- generation of TH2 cytokines.
mation that initiate and drive many pathological disorders.45 TNF IL-­33 induces chemokine CCL11 (eotaxin), IL-­8 and MCP-­1, and
can provoke differentiation at sites of injury, necrosis, apoptosis, the cytokine IL-­6 in human fibroblasts and increases IL-­6 and TNF
oxidative stress, tissue remodelling, cell proliferation, cachexia, in keratinocytes.54
CONTI et al. |
      5 of 8

IL-­33 is elevated in the serum level of patients affected by organ increase in stimulation of macrophage cells in vitro to produce more
fibrosis and can be a serum marker for vascular dysfunctions, al- inflammatory cytokines. This cytokine, which uses IL-­18 receptor
though sometimes, for unknown reasons, IL-­33 in fibrosis is not high. alpha (IL-­18Rα), does not act as an anti-­receptor, but as an endocel-
IL-­33 is involved in collagen generation and mast cell recruitment lular inhibitor acting on TIR8.
and activation, as well as in induction of IL-­4, IL-­5 and IL-­13. IL-­33 and IL-­
37 downregulates and silences inflammatory cytokines in
its receptor ST2 are upregulated in myofibroblasts where it stimu- monocytes and other cells. 58 IL-­37 transgenic mice are protected
lates TGF-­β1, IL-­1 and TNF. It has been reported that IL-­33 polarizes against LPS treatment, present less inflammation and are more
M2 macrophages and upregulates the transcription of TGF-­β1.42 resistant to infection, cardiovascular and liver diseases.58 This is
Tissue fibrosis is associated with the biological inflammatory effects due to its effect on the inhibition of inflammatory cytokines and
+
of IL-­33 produced by macrophages and CD8 T cells as well as by chemokines, along with the stimulation of IL-­10 which is also an anti-­
MCs present in the tissue. Activation of MCs leads to the genera- inflammatory cytokine. IL-­37 is not only an inhibitor of innate im-
tion and release of IL-­33 that is related to collagen synthesis, and munity but also inhibits adaptive immunity, since it downregulates
mice that are genetically free of IL-­33 (IL-­33−/−) are largely protected antigen presenting cells (APC) and the activation of regulatory T
from experimentally induced fibrosis. This is because IL-­33 may in- cells (Tregs). The inhibitory effect of IL-­37 is due to its suppression
duce IL-­13, IL-­6 and TGF-­β.32 Therefore, high serum levels of ST2 of MyD88-­mediated inflammatory responses and, consequently, to
or IL-­33 are considered a fibrinogenic prognostic factor. In addition, the inhibition of NF-­κB induced through TLR2 or TLR4, a mechanism
activated MCs release chemical mediators and cytokines, which dependent of IL-­18Rα.59 Therefore, IL-­37 may be useful for suppres-
provoke VEGF generation, stimulate vascular cells, and participate sion of inflammatory diseases induced by MyD88-­dependent TLR
in angiogenesis.55 signalling7 (Figure 2).
IL-­33 is a fundamental cytokine in allergic and inflammatory dis- In the inflammatory response, macrophages generate IL-­1 which
eases and it is a profibrotic protein. Targeting IL-­33 is important to activates mast cells to produce inflammatory IL-­6 and TNF in the
ameliorate progressive type 2-­driven diseases, including fibrosis of site.60 IL-­37 may play a role in this activation and in certain infec-
tissues and organs. tions and inflammatory disorders by inhibiting the production of
proinflammatory cytokines, including IL-­1 MC release and TNF.61 IL-­
37 protects against septic shock and colitis and suppresses inflam-
7 | I L-­3 7 I N H I B IT S FI B ROS I S matory responses to Toll-­like receptor (TLR) agonists.56 In addition,
IL-­37 inhibits the production of inflammatory cytokine IL-­1 family
IL-­37 (or ILF7), which is located in the cell nucleus, is present in in- members induced by TLR4. In IL-­37 knockdown mice there is an in-
flammatory processes and is an inhibitor of the inflammatory re- crease in IL-­1 produced by TLR4.56
sponse.52,56 IL-­37 is made of 5 proteins, of which IL-­37b is the most Therefore, inflammatory cytokines are suppressed by IL-­37 by
important and most studied.57 The inhibition of IL-­37 leads to an inhibiting MyD88, which is a TLR2-­dependent factor, and reduce

F I G U R E   2   Production of anti-­
inflammatory and proinflammatory
cytokines. Macrophage activation releases
IL-­37 which inhibits MyD88. Dendritic
cells activated after maturation release
proinflammatory and anti-­inflammatory
cytokines. Proinflammatory IL-­1 family
members are inhibited by IL-­37 generated
by activated macrophage
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6 of 8       CONTI et al.

inflammatory mediator production following stimulation of TLR2 ORCID

7
and TLR4.
P. Conti  http://orcid.org/0000-0002-9475-4924
Targeting proinflammatory IL-­1 family members in innate immunity,
IL-­37 may be useful in anti-­inflammatory therapy since rodents treated
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