Potential Therapeutic Aspects of Alarmin Cytokine Interleukin 33 or Its Inhibitors in Various Diseases

Clinical Therapeutics/Volume 38, Number 5, 2016

Review Article

Potential Therapeutic Aspects of Alarmin Cytokine Interleukin 33 or Its Inhibitors in Various Diseases Muhammad Imran Arshad, PhD1,2,3,4; Hilal Ahmad Khan, MBBS4; Gregory Noel, PhD1,2,3; Claire Piquet-Pellorce, PhD1,2,3; and Michel Samson, PhD1,2,3 1

Institut National de la Sante´ et de la Recherche Me´dicale (Inserm), Institut de Recherche Sante´ Environnement Travail (IRSET), Rennes, France; 2Universite´ de Rennes 1, Rennes, France; 3Structure Fe´de´rative BioSit UMS 3480 CNRS-US18 Inserm, Rennes, France; and 4Institute of Microbiology, University of Agriculture, Faisalabad, Pakistan ABSTRACT Purpose: The purpose of this review was to examine the comprehensively accumulated data regarding potential therapeutic aspects of exogenous administration of interleukin 33 (IL-33) or its antagonists in allergic, cancerous, infectious, and inflammatory diseases. Methods: A selected review was undertaken of publications that examined the protective and exacerbating effects of IL-33 or its inhibitors in different diseases. Mechanisms of action are summarized to examine the putative role of IL-33 in various diseases. Findings: IL-33 promoted antibacterial, antiviral, anti-inflammatory, and vaccine adjuvant functions. However, in TH2-biased respiratory, allergic, parasitic, and inflammatory conditions, IL-33 exhibited disease-sensitizing effects. The alarmin cytokine IL-33 induced protective effects in diseases via recruitment of regulatory T cells; antiviral CD8þ cells, natural killer cells, γδ T cells, and nuocytes; antibacterial and antifungal neutrophils or macrophages; vaccineassociated B/T cells; and inhibition of nuclear factor–κB–mediated gene transcription. In contrast, IL-33 exacerbated the disease process by increasing TH2 cytokines, IgE and eosinophilic immune responses, and inhibition of leukocyte recruitment in various diseases.

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Implications: The protective or exacerbated aspects of use of IL-33 or its inhibitors are dependent on the type of infection or inflammatory condition, duration of disease (acute or chronic), organ involved, cytokine microenvironment, dose or kinetics of IL-33, and genetic predisposition. The alarmin cytokine IL-33 acts at cellular, molecular, and transcriptional levels to mediate pluripotent functions in various diseases and has potential therapeutic value to mitigate the disease process. (Clin Ther. 2016;38:1000–1016) & 2016 Elsevier HS Journals, Inc. All rights reserved. Key words: diseases, IL-33, immunity, therapeutic aspects.

INTRODUCTION The alarmins or danger signals are defined as the class of molecules that alert the immune system to circumvent the invading antigens in the host. The term alarmin was first described in 20051 as a class of structurally diverse and pluripotent host proteins.2 Defensins, eosinophil-derived neurotoxin, cathelicidins, interleukin (IL) 1α, cytosolic calcium-binding proteins of the S100 family, heat-shock proteins, and HMGB1 protein were known to be the classic examples of alarmins.1,3

Accepted for publication February 17, 2016. http://dx.doi.org/10.1016/j.clinthera.2016.02.021 0149-2918/$ - see front matter & 2016 Elsevier HS Journals, Inc. All rights reserved.

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M.I. Arshad et al. The cytokine IL-33 is the 11th described member of the IL-1 family and is designated as IL-1F11. IL-33 was originally identified as DVS27, a gene that was up-regulated in vasospastic cerebral arteries after subarachnoid hemorrhage in canines,4 and as a nuclear factor from high endothelial venules, which is expressed in endothelial cells nuclei.5 In 2005, the DVS27 gene was rediscovered as IL-33 by using computational tools on the basis of sequences that contained the 12 β-trefoil structure seen in IL-1/ fibroblast growth factor–like proteins.2 The cytokine IL-33 was described as an alarmin with a dual function protein that acts as a cytokine when released from cells and a nuclear factor–regulating gene transcription.6 Once released from cells, the cytokine functions of IL-33 are mediated by interaction with its specific receptors, including ST2 (IL-1 receptor–like 1) and IL-1RAcP (IL-1 receptor accessory protein). The cellular sources of IL-33 include endothelial cells, epithelial cells, smooth muscle cells, keratinocytes, astrocytes, adipocytes, fibroblasts, hepatic and pancreatic stellate cells, monocytes, macrophages, and hepatocytes.7–10 The target cells of IL-33 include B cells, TH2 cells, CD8þT cells, macrophages, dendritic cells, mast cells, basophils, and a recently identified population of innate lymphoid cells called nuocytes in different tissues, including lungs, gut, liver, spleen, or skin.2,11–16 Extracellular IL-33 induces autocrine, paracrine, and juxtacrine actions that are important in autoimmune or inflammatory diseases, immune defense, and repair mechanisms.16,17 The underlying signaling pathway of the IL-33/ST2 axis is dependent on activation of cytoplasmic TIR domain, such as MyD88 and the serine threonine kinases IRAK1, IRAK4, and TRAF6, leading to activation of nuclear factor–κB (NF-κB), AP-1, and mitogen-activated protein kinase (MAPK) pathways. The nuclear functions of IL-33 are associated with down-regulation of NFκB–dependent gene transcription.18 IL-33 was used as a promising mucosal vaccine adjuvant and induced protective immunity (i.e., primary and memory immune responses).19 The mouse Il33 gene revealed the existence of two transcripts, IL-33a and IL-33b, with different 5'UTRs but coding for the same protein. The IL-33a and IL-33b mRNAs started with two different noncoding first exons, distant by 20 kb. A consensus TATA-like sequence was found 29 bp upstream of each of these transcription start sites, evidencing that IL-33a and

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IL-33b are transcribed from classic TATA box–containing promoters.20 IL-33 was found to be synthesized as a 270–amino acid protein precursor containing an N-terminal nuclear localization sequence, a helix-turn helix motif, and a C-terminal region with structural homology to other IL-1 cytokines (IL-1α, IL-1β, and IL18).2,5 The human and mouse IL-33 shared a 55% homology at the amino acid level. The translated fulllength IL-33 protein (30.7 kDa) was found to be a nuclear factor associated with heterochromatin in vivo and mitotic chromosomes in living cells, which possesses potent transcriptional-repressor properties.6,21 The protective functions of IL-33 plausibly attributed to its binding to acidic pocket of a dimeric histone, H2AH2B, on the surface of nucleosomes, resulting in suppression of gene transcription.21,22 Accordingly, IL-33 interacts with transcription factor NF-κB (p65 subunit) and impaired its DNA binding, resulting in diminished NF-κB–dependent proinflammatory gene transcription.18 IL-33 was described as an alarmin in different pathologic conditions or infectious diseases,23 and it induces multivalent functions, resulting in proinflammatory or anti-inflammatory effects in various conditions.24 The full-length bioactive form of IL-33 was released during cell necrosis and act as an endogenous danger signal or alarmin.6,25,26 It was found that apoptotic caspases cleave IL-33 and rendered it inactive or nonfunctional.25,27 IL-33 was also cleaved by neutrophil elastase and cathepsin G, mast cell chymase enzyme, and calpain enzyme as previously described.28–31 Recently, IL-33 was found to be associated with a form of cell death called necroptosis as inhibitors of necroptosis (necrostatin-1 and PJ34) down-regulated IL-33 expression in liver injury.32 These studies described the activity of endogenous IL-33, but exogenous administration of IL-33 induced dual edge functions, depending on the immune pathology or organ involved. Although IL-33 has been extensively studied in various diseases, a comprehensive review on therapeutic implications of IL-33 and its mechanism of action in different conditions remained obscure. Therefore, based on our and other published data, we summarized a review on the effect of therapeutic administration of IL-33 or blocking of IL-33/ST2 during infectious, allergic, and inflammatory diseases (Figure). The protective and exacerbating or sensitizing role of IL-33 administration in immunopathologic animal disease models and respective mechanism of action is elaborated comprehensively in this review.

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Exogenous IL-33 administration

IL-33

IL-33

IL-33 IL-33 IL-33

ST2 IL-33

IL-33

IL-33 or ST2 blocking antibodies

IL-33

IL-33

IL33

IL-3 3

ST2s

IL-33

IL-1RAcP

ST2L

ST2L

IL-1RAcP

IL-33

PROTECTIVE EFFECTS EXACERBATUNG EFFECTS Airway allergy Lung fibrosis Influenza virus lung infection Respiratory syncytial virus infection Acute kindeny injury UIcerative colitis Intestinal mucositis Eosinophilic esophagitis Exoperimental autoimmune encephalomyelitis Graft-versus-host disease Periodontal disease Schistosoma japonicum infection Leishmaniasis (Leishmania donovani) Formalin-induced pain

Tumor growth and metastasis Adipose tissue inflammation Atherosclerosis

Joint inflammation/arthritis LCMV infection and hepatitis Adenovital hepatitis Ischemia/reperfusion hepatitis Concanvalin A−induced hepatitis Skin infection by Staphylococcus auerus Keratitis by Pseudomonas aeruginosa Fungal peritonitis Pancreatitis Intestinal inflammation Colitis Intestinal nematode infection Experimental sepsis by cecal ligation puncture Ischemic brain injury/stroke HDM-induced airway inflammation Influenza virus vaccine Immune-mediated experimetnal arthritis Rheumatoid arhritis Nippostrongylus brasiliensis intestinal infection Leishmaniasis (Leishmania major) Meningitis Systemic lupus erythematosus HDM asthma Ovalbumin-induced airway inflammation Allergic rhinitis Fungal asthma Cigarette smoke-induced lung inflammation

Figure. Potential protective or sensitizing effects of exogenous administration of interleukin (IL)-33 or blocking of IL-33/ST2 in diverse diseases. HDM, house dust mite; LMCV, lymphocytic choriomeningitis virus.

Protective Therapeutic Role of IL-33 or Its Inhibitors in Various Diseases

Beneficial Effects of IL-33 Administration in Different Diseases

The dichotomous role of IL-33 in various diseases is evident from previous studies; the exogenous administration of IL-33 induced protective effects during cancerous, infectious, allergic, and inflammatory diseases (Table I and Figure).

IL-33 favored antitumor immune response through enhancement and activation of effector cytotoxic T lymphocyte, natural killer (NK) cells, and interferon (IFN)-γ production, resulting in regression of B16 melanoma, Lewis lung carcinoma, and human

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Table I. Protective effects of IL-33 or its inhibitors in cancerous, infectious, allergic, and inflammatory diseases. Disease

Role of IL-33 or ST2 Inhibitors

Beneficial effects of exogenous IL-33 in different diseases Tumor growth and metastasis Protective (B16 melanoma and Lewis lung carcinoma metastatic model)

HPV-associated cancer model

Protective, vaccine adjuvant– enhancing and antitumor effect

Adipose tissue inflammation

Protective, in genetically obese mice

Atherosclerosis

Protective

Joint inflammation or arthritis

Protective

LCMV hepatitis

Protective (in acute phase at 16 hours)

Mechanism of Action

Reference

Activation of CD8þ T cells and NK cells with increased infiltration in tumor tissues. Increased cytotoxicity of CD8þ T cells and NK cells in vitro via NF-κB and up-regulated expression of CD69. Enhanced antigen-specific effector and memory T cells (CD4þ and CD8þ) in vivo. Increased antiviral IFN-γ production and HPV induced tumor regression. Decreased adiposity and deceased fasting glucose level. Improvement in glucose level and insulin tolerance. Accumulation of TH2 cells in adipose tissue and polarization of macrophages toward M2 activated phenotype (CD206þ). Decreased inflamed atherosclerotic plaques. Decreased IFN-γ level and enhanced TH2 cytokines (IL-4, IL-5 and IL-13). Increased serum IgA, IgE, and IgG1 level and antioxidized lipoprotein antibodies. Inhibition of cartilage destruction, systemic bone loss, and osteoclast differentiation. IL-33 increased antiosteoclastogenic cytokines, such as GM-CSF, IL-4 and IFN-γ in serum. Increased IFN-γ–producing γδ T cells and NK cells and inhibition of IL-17þ γδ T cells, dendritic cells proliferation, and cytokine production. The above protective effects were reversed in IL-33 knockout mice.

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Table I. (continued). Disease LCMV infection

Adenoviral hepatitis

Warm ischemia or reperfusion liver injury

Ischemia/reperfusion hepatitis (acute)

ConA–induced hepatitis (acute)

Skin infection by methicillinresistant Staphylococcus aureus

Keratitis (Pseudomonas aeruginosa)

Role of IL-33 or ST2 Inhibitors

Mechanism of Action

Protective, antiviral, and vaccine Enhanced antigen-specific CD8þ or cytotoxic T-cell functions. adjuvant effect IL-33 favored immunomodulatory effect. Protective Decreased serum ALT, TNF-α level, and councilman bodies in liver. Decreased infiltration of macrophages, dendritic cells, and NK cells in liver and enhanced number of Treg cells and nuocytes in liver. Protective, mouse IL-33 injection Decreased AST, ALT, and IFN-γ in male Balb/C mice level. Increased IL-4, IL-5, and IL-13 production. Treatment with anti-ST2 antibody worsens the disease severity. Protective, i.p. injection in Increased activation of NFκB, C57Bl/6 male mice MAPK, cyclin D, and BCl2 genes in liver. Dampen the CXC chemokines and liver neutrophil accumulation. Protective, mouse IL-33 injection Decreased serum AST, ALT, and (1 μg per mouse i.p.) in TH1/TH17 cytokines. Downregulation of infiltration of Balb/C mice mononuclear cells in liver and increased number of Treg cells and IL-4 producing CD4þ T lymphocytes in liver. ST2 knockout mice had exacerbated liver injury. IL-33 knockout mice were more susceptible to ConA liver injury than WT mice. Protective Enhanced bacterial clearance and wound healing by upregulation of CXCR2 expression on neutrophils and their recruitment to site of infection. Protective Better bacterial control by increased polarization of M2 macrophages and TH2 cytokines (IL-4, IL-5, and IL-10) expression in C57Bl/6 mice.

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42,56

43

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Table I. (continued). Disease Fungal peritonitis (Candida albicans)

Role of IL-33 or ST2 Inhibitors Protective

Mechanism of Action

Enhanced fungal clearance and survival of mice. IL-33 upregulated expression of CXCL1 and CXCL2 on neutrophils, increased complement receptor-3, and ROS production, leading to yeast phagocytosis and killing. Pancreatitis (Coxsackie B virus) Protective Prevented pancreatitis by enhancing number of CD8þ T cells, NK cells, and upregulation of IL-4–, TNF-α–, and IFN-γ–dependent antiviral immune response. Intestinal inflammation Protective IL-33 administration ameliorated intestinal inflammation in amphiregulin-dependent manner. Experimental colitis Protective IL-33 increased the expression of (trinitrobenzene sulfonic TH2 cytokines, increase in FoxP3 acid–induced acute colitis) expression in Treg cells. Switched TH1 cytokine signature to TH2 cytokines via Treg cells. Enhanced number of CD103þ dendritic cells in intestine. DSS colitis (chronic) Protective, repeated mouse IL-33 Decreased inflammation and TH1 treatment at intermediate and cytokines (IFN-γ) and enhanced after DSS challenge TH2 cytokine expression. Enhanced Ly6g mRNA expression and myeloperoxidase activity in colon. Intestinal nematode infection Protective Increased expulsion of parasites (Trichuris muris) from gut. Decreased TH1 cytokines and pro-TH2 (IL-4, IL-9, and IL-13) response in intestine via overexpression of thymic stromal lymphopoietin in intestinal epithelium. Experimental sepsis by cecal Protective, intravenous mouse Increased neutrophil influx at site ligation puncture IL-33 administration (1 μg per of infection and efficient mouse, Balb/C) bacterial clearance. IL-33 prevented down-regulation of CXCR2 expression and chemotaxis, peritonitis, and mortality in mice.

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Table I. (continued). Disease

Role of IL-33 or ST2 Inhibitors

Ischemic brain injury or stroke Protective role of recombinant (acute phase) IL-33 administration in C57Bl/6 male mice

HDM-induced airway inflammation

Protective role of recombinant IL-33 administration in Balb/C mice

Influenza virus vaccine

Protective, adjuvant, and immunostimulatory effect

Beneficial effects of blocking IL-33 or its receptor ST2 in different Immune-mediated experimental No effect of genetic IL-33 arthritis (antigen and deficiency collagen mediated by injection of methylated bovine serum) Rheumatoid arthritis (collagen Protective effect of anti-ST2 induced) antibody Nippostrongylus brasiliensis intestinal infection

Limited protective effect due to genetic deficiency of IL-33

Leishmaniasis (Leishmania major) No effect of anti–ST2-Fc blocking antibody

Meningitis (angiostrongyliasis)

Systemic lupus erythematosus (chronic disease)

Protective effect of anti-ST2 antibody, 3 days after infection Protective effect of anti–IL-33 antibody for 6 weeks (i.p.) in MRL/lpr lupus-susceptible mice

Mechanism of Action

Reference

IL-33 ameliorated ischemic brain damage at 24-72 hours, inflammation, and neurologic deficit. IL-33 decreased TH17 cytokines and promoted TH2 immune response. IL-33 favored antibody production and augmented neutralizing humoral immune response. IL-33 adjuvanted with influenza virus vaccine enhanced IgG, IgA, TH1, and TH2 cytokines. diseases IL-33 deficiency in mice did not impair or affect antigen- and collagen-mediated arthritis. May enhance the antigenspecific IFN-γ and IgG2a production. Decreased IFN-γ production and collagen-induced arthritis or inflammation. Limited N brasiliensis clearance and decreased IL-13 production in IL-33 knockout mice. Impaired RELMβ expression and eosinophil recruitment. Enhanced TH1 response (IFN-γ) by CD4þ T cells without impairment of TH2 cytokine production. Decreased IL-5 in circulation and decreased eosinophilic influx in meninges. Decreased proteinuria, anti–doublestranded DNA antibodies and prevented antigen-antibody complex formation. IL-33– blocking antibody decreased TH17 cytokines, IL-1β, and IL-6 and enhanced the number of Treg and myeloid derived suppressor cells.

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19

54

55

57

58

59

60

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Table I. (continued). Disease HDM asthma mouse model (Balb/C)

Airway inflammation (ovalbumin-mediated, chronic condition) Airway inflammation (ovalbumin mediated)

Allergic rhinitis (ovalbumin induced)

Fungal asthma (Aspergillus fumigatus)

Cigarette smoke–induced lung inflammation

Role of IL-33 or ST2 Inhibitors Anti–IL-33 priming in mice by s.c. route

Mechanism of Action

Anti–IL-33 IgG decreased airway hyperresponsiveness by decreasing eosinophils in BALF and decrease of inflammatory cytokine production (IL-17A, IL-25, and IL-33) in lungs Protective effect of anti-ST2 Decreased IgE-mediated airway antibody or anti–IL-33 inflammation or remodeling antibody treatment by control of IL-33–producing alveolar macrophages. Protective effect of anti–IL-33 Reduced eosinophils and antibody (150 μg per mouse) lymphocytes in lungs and or anti-ST2 monoclonal decreased IL-4, IL-5, and IL-13 antibody treatment in Balb/C in BALF. Decreased level of female mice ovalbumin-specific IgE antibodies in serum. Protective effect of anti–IL-33 Anti–IL-33 antibody decreased antibody treatment rhinitis, improved skin denudation and nociception, decreased IgE level, and reduced eosinophilia and IL-4, IL-5, and IL-13 production in bronchoalveolar lavage or in nasal cavity. Switch from proinflammatory Protective effect of anti-ST2L TH2 response to protective monoclonal antibody with TH1 response by activation of CpG Toll-like receptor 9 on innate immune cells. Protective effect of anti–IL-33 Blocking IL-33 led to decrease antibody by intranasal route neutrophil and macrophage infiltration in lungs and decreased expression of MCP-1, IL-1β, TNF-α, IL-17, and mucin-5.

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62,65

64

66

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ALT ¼ alanine aminotransferase; AST ¼ aspartate aminotransferase; ConA ¼ concanavalin A; DSS ¼ dextran sulfate sodium; GM-CSF ¼ granulocyte-macrophage colony-stimulating factor; HDM ¼ house dust mite; HPV ¼ human papillomavirus; IFN-γ ¼ interferon-γ; IL ¼ interleukin; LCMV ¼ lymphocytic choriomeningitis virus; NF-κB ¼ nuclear factor–κB; NK ¼ natural killer; TNF-α ¼ tumor necrosis factor-α; Treg ¼ T regulatory; WT ¼ wild type.

papillomavirus (HPV)–associated tumors.33,34 As a vaccine adjuvant, IL-33 enhanced specific cellular immune responses (effector and memory T-cell

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functions) against HPV-associated cancer model.34 In genetically obese mice, IL-33 promoted a pro-TH2 cellular immune response, macrophage polarization,

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Clinical Therapeutics and decreased adipose tissue inflammation, revealing a protective effect of IL-33 during obesity.35 IL-33 was found to be cardioprotective because IL-33 inhibited formation of atherosclerotic plaques and favored a TH2 response or antioxidized lipoprotein humoral immune response.36 The exogenous administration of IL-33 inhibited joint inflammation by upregulation of anticlastogenic cytokines, such as IL-4, granulocyte-macrophage colony-stimulating factor, and IFN-γ.37 These findings suggested a divergent role of IL-33 in arthritis. In liver disease, the IL-33/ST2 axis was known to be hepatoprotective. In lymphocytic choriomeningitis virus–induced acute hepatitis, IL-33 induced hepatoprotection via increased infiltration of IFN-γ–producing γδ T cells and NK cells in liver, which mediated antiviral immune response.38 IL-33 favored antiviral and vaccine adjuvant effect during lymphocytic choriomeningitis virus infection by activation of cytotoxic T lymphocytes and immune-modulatory functions.39 In the adenoviral hepatic model, IL-33 diminished liver injury marker (ALT), tumor necrosis factor-α, liver infiltrate cells, and an increased number of regulatory T (Treg) cells and innate lymphoid cells and nuocytes.38 The protective functions of IL-33 were found in ischemia/reperfusion liver injury, which were associated with decreased aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, dampened chemokine and neutrophil infiltration, and pro-TH2 and NF-κB/MAPK responses in the liver.40,41 In concanavalin A (ConA)–mediated immune hepatitis, IL-33 ameliorated liver injury by decreasing AST and ALT, TH1 and TH17 cytokines, and promotion of Treg cell or IL-4–producing CD4þ cells in the liver.42 Hence, IL-33 orchestrated immune functions in the liver at cellular, molecular, and gene transcriptional levels to protect hepatitis. IL-33 induces protective functions in bacterial, fungal, and parasitic infections. The methicillinresistant Staphylococcus aureus–associated skin infection was improved by IL-33 by promoting bacterial clearance, wound healing, and neutrophil recruitment at the site of infection.43 Better control of Pseudomonas aeruginosa–induced keratitis was found after IL-33 treatment, which enhanced macrophage polarization and functions and pro-TH2 immune response.44 In the fungal peritonitis infection model by Candida albicans, IL-33 promoted fungal clearance via increased neutrophil infiltration and its killing

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by the ROS-dependent pathway or oxidative burst mechanism.45 In gastrointestinal diseases, IL-33 mediated a protective therapeutic effect. In Coxsackie B virus–induced pancreatitis, IL-33 abrogated pancreatic inflammation via up-regulation of antiviral cytokine response (IL-4, tumor necrosis factor-α, and IFN-γ dependent) and CD8þ cells, NK cells dependent mechanism.46 A protective mechanism dependent of amphiregulin was boosted by IL-33 administration to dampen the intestinal inflammation.47 In an animal model of experimental colitis, single or repeated injections of IL-33 proved protective in acute and chronic colitis.48,49 The underlying mechanism was switching of TH1 cytokine responses to TH2 biased immune responses, recruitment of Treg cells, and increased myeloperoxidase activity.48,49 IL-33 was protective by expelling Trichuris muris nematodes from the gastrointestinal tract in a TH2 cytokine– dependent mechanism.50 In the septic condition, IL-33 enhanced influx of neutrophils and prevented cecal ligation puncture–induced sepsis in mice.51 In acute ischemic brain injury or stroke, IL-33 provided protection by decreasing inflammatory cytokines (TH17) or inflammation.52 IL-33 administration promoted humoral immune response against house dust mite– induced airway inflammation as recently described.53 As a vaccine adjuvant in influenza virus infection, IL-33 enhanced antiviral humoral and cytokinic immune response.19

Beneficial Effects of Blocking IL-33 or ST2 in Different Diseases The potent role of IL-33 during arthritis was evidenced in previous studies; however, the genetic deficiency of IL-33 did not affect collagen-induced arthritis,54 and anti–ST2 antibody treatment protected mice against collagen-induced arthritis.55 In liver disease, the genetic ablation of IL-33 or ST2 sensitized the mice to develop enhanced ConA liver injury compared with WT mice.42,56 In the context of parasitic infections, the genetic deficiency of IL-33 led to impaired clearance of Nippostrongylus brasiliensis intestinal infection,57 whereas in an antagonistic approach, the use of ST2-Fc blocking antibody did not affect leishmaniasis infection in mice.58 In another antagonistic strategy, anti–ST2 antibody decreased eosinophilic response and meningitis caused by Angiostrongylus systemic parasitic infection.59

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M.I. Arshad et al. Blockade of IL-33 prevented chronic systemic lupus erythematosus in lupus-susceptible mice by inhibition of TH17, proinflammatory cytokines, and recruitment of Treg cells.60 In respiratory diseases, blocking of IL-33 activity proved to be more effective. In the house dust mite asthma model, anti–IL-33 priming was protective by decreasing airway hyperresponsiveness, eosinophilia, and inflammatory cytokines.61 Antagonizing the IL-33 (anti-ST2 or anti–IL-33 injection) induced protective effects in ovalbumin-mediated airway inflammation and allergic rhinitis,62–65 the underlying mechanism was dependent on decreased IgE and TH2 cytokine production. Anti–IL-33 treatment ameliorated fungal asthma by Aspergillus fumigatus in a TH2-dependent manner.66 Similarly, the cigarette smoke–mediated experimental lung inflammation was inhibited by blocking IL-33, which was associated with decreased neutrophil and macrophage infiltration in lungs and down-regulation of inflammatory mediators.67 Conclusively, IL-33 or its inhibitors induced protective effects in a wide range of diseases mainly by mediation of cellular and molecular immune responses. Mechanistically, IL-33 promoted infiltration of regulatory T cells; antiviral CD8þ cells, NK cells, γδ T cells, and nuocytes; neutrophils and macrophagemediated antibacterial and antifungal responses, and vaccine adjuvanted humoral and memory lymphocytic immune responses. IL-33 inhibited proinflammatory cytokines and inflammatory mediators in various organs and tissues after injury or infection and regulated NF-κB gene transcription to control inflammation. However, in allergic or infectious diseases of the respiratory tract, IL-33 blockade induced protective effects by decreasing IgE, eosinophils, and TH2 cytokine production.

EXACERBATING ROLE OF IL-33 IN VARIOUS DISEASES In contrast to protective functions or effects induced by IL-33, the administration of exogenous IL-33 may have exacerbating aspects in different diseases (Table II and Figure). IL-33 aggravated ovalbumin- or Alternaria alternata–mediated airway allergy or inflammation by enhancement of TH2 cytokine (IL-4, IL-5, IL-13)– dependent allergic response.68,69 Profibrotic effect of IL-33 was observed in bleomycin-induced lung fibrosis with augmented IL-13 and transforming

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growth factor-β1 production.70 In viral lung infections (by influenza virus or respiratory syncytial virus), IL-33 caused the mice to develop severe inflammation, increased airway hyperresponsiveness, TH2 cytokines, and eosinophilic immune responses in lungs of infected mice.71,72 IL-33 exacerbated acute cisplatin-induced kidney injury by increasing apoptotic and necrotic tubular cell death and cellular infiltration.73 Although IL-33 induced hepatoprotective effects (Table I), Chen et al found that increased ConAinduced liver injury (AST and ALT) with a higher dose of IL-33 (10 μg per mouse) and blocking IL-33 (by anti–IL-33 or anti–ST2-Fc antibody) abrogated the liver injury markers.74 Our previous data revealed that deficiency of IL-33 caused the mice to enhanced ConA liver injury, indicating a protective effect of endogenous IL-33 in liver disease.56 The plausible differences of the study by Chen et al with other data may be attributed to the dose of IL-33 or ConA used in these studies, genetic background of mice, and kinetics of liver injury. However, it is evident from most of the studies that the IL-33/ST2 axis induced hepatoprotective effects during viral, ischemic, and immune-mediated hepatitis.38,40–42,75 In contrast to chronic colitis, IL-33 exacerbated dextran sulfate sodium–induced acute colitis with upregulation of proinflammatory immune responses.76,77 Similarly, IL-33 administration sensitized the mice to irinotecan-induced intestinal mucositis with decreased leukocyte number. The blockade of ST2 or IL-33 ameliorated the disease severity by decreasing chemokine production and restricting neutrophil infiltration.78 In acute esophagitis, IL-33 favored pro-TH2 and eosinophilic response to exacerbate the disease.79 Moreover, IL-33 sensitized the mice to increased autoimmune encephalomyelitis via enhanced IFN-γ and IL-17 production.80 In graft-versus-host disease, IL-33 caused the mice to have a severe inflammatory response, and antagonistic IL-33 approaches reversed the inflammatory condition.81 IL-33 enhanced periodontal bone loss in Porphyromonas gingivalis infected mice through up-regulated receptor activator of NF-κB ligand expression in B and T lymphocytes in gingival mucosa,82 which was abolished in ST2 knockout mice. In parasitic infections, IL-33 sensitized the mice to increased TH2 response and liver disease caused by Schistosoma japonicum,83 and antagonizing the IL-33 proved protective. The visceral leishmaniasis by Leishmania

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Table II. Exacerbating effects of IL-33 in different diseases. Disease

Role of IL-33

Airway allergy (by ovalbumin or Alternaria alternata extract sensitization)

Exacerbating

Airway inflammation

Sensitizing

Lung fibrosis (bleomycin induced)

Exacerbating or profibrotic

Influenza virus lung infection

Exacerbating

Respiratory syncytial virus infection

Exacerbating

Acute kidney injury (cisplatin induced)

Exacerbating

ConA-induced hepatitis (acute)

Exacerbating, mouse IL-33 injection (10 μg per mouse) in C57Bl/6 mice

Mechanism of action

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IL-33 administration abrogated Heligmosomoides polygyrus mediated suppression of Alternaria and ovalbumininduced airway allergic response (IL-4, IL-5, IL-13 production and localized eosinophilia). Enhanced allergic response or airway hyperresponsiveness and goblet cell hyperplasia in lungs accompanied by IL-4, IL-5, and IL-13 secretion in lungs after IL-33 administration. IL-33 promoted lung inflammation and profibrogenic response (increase in IL-13 and TGF-β1 expression). Blocking IL-33 antibody or use of ST2 knockout mice revealed antifibrotic effects. Impaired lung function and repair in IL-5, IL-9, IL-13, and amphiregulin-dependent manner. Enhanced the disease severity and inflammation of the respiratory tract. Anti–IL-33 antibody treatment inhibited airway hyperresponsiveness, TH2 cytokines, eosinophilia, and mucous hyperproduction in airways. IL-33 markedly exacerbated acute tubular necrosis and apoptosis, serum creatinine level, and infiltration of CD4þ T cells. Increased serum AST and ALT levels in mouse IL-33 and ConA–treated mice. Anti–IL-33 antibody (300 μg per mouse) or anti–ST2-Fc antibody

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Table II. (continued). Disease

Role of IL-33

DSS colitis (acute), ulcerative colitis

Exacerbating

DSS-induced colitis (acute)

Exacerbating (in acute phase)

Intestinal mucositis (irinotecan Exacerbating, IL-33 injection Camptothecin-II induced) (200 ng per mouse) in Balb/C mice

Eosinophilic esophagitis (acute Exacerbating (use of onset) recombinant IL-33 for 1 week)

Experimental autoimmune Sensitizing or exacerbating encephalomyelitis, myelin oligodendrocyte glycoprotein (MOG 35-55) peptide mouse model Graft-versus-host disease

Sensitizing or exacerbating

Periodontal disease (periodontitis)

Exacerbating

Mechanism of action (50 μg per mouse) decreased liver injury markers (AST and ALT). Augmented colon inflammation in an IL-4–dependent manner with increased IL-1, IL-4, IL-6, IL-13, and IL-17 cytokines and VEGF. Decreased CXCL9 and CXCL10 expression. Decreased IFN-γ and IL-17A producing lymphocytes in lamina propria of colon. Increased IL-5 and IL-13 production. Increased mucositis associated with severe systemic leucopenia, shortened villi, and increased plasma leakage. The mucositis was decreased in ST2 knockout mice or in mice treated with anti–IL-33 antibody or sST2 with reduced neutrophil accumulation and the production of CXCL1, CXCL2, and CCL2 chemokines. Eosinophilia, mucosal hyperproliferation, increased TH2 cytokines (eg, IL-13) and decreased T-regulatory signature. Exacerbated disease severity associated with increased IFN-γ and IL-17 production. Blocking anti–IL-33 antibody reversed the above phenomenon and disease. Increased inflammation after recombinant IL-33 injection. The lethality and inflammation were decreased in IL-33–/ST2deficient mice or by ST2-Fc antibody injection. Porphyromonas gingivalis infected mice had enhanced alveolar

Reference

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77

78

79

80

81

82 (continued)

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Table II. (continued). Disease

Schistosoma japonicum infection

Leishmaniasis (Leishmania donovani)

Formalin-induced pain

Role of IL-33

Mechanism of action

bone loss or periodontal bone destruction. Increased receptor activator of NF-κB ligand expression in B and T lymphocytes in gingival tissues after mouse IL-33 treatment. Decreased periodontal loss was found in ST2 knockout mice. Exacerbating IL-33 increased expression of TH2 cytokines (IL-5, IL-10, and IL13) at 6 weeks after infection with increased liver disease. Anti–IL-33 treatment reversed the above parameters to normal. Exacerbating with increased Decreased TH1 cytokines inhibit monocyte ad neutrophil susceptibility, i.p., 2-week recruitment in liver (decreased treatment in Balb/C mice KC/CXCL1 and CXCL2 expression). The parasitic load and granuloma formation in liver were diminished in ST2 knockout mice. Sensitizing (administration of s. IL-33 administration enhanced c. mouse IL-33, 300 ng per pain sensation with increased mouse, and intrathecal paw lifting and licking time in mouse IL-33, 3 ng per mouse) normal and formalin-injected mice. ST2 antibody treatment or ST2 deficiency in mice alleviated pain sensation and behavior.

Reference

83

84

85

ALT ¼ alanine aminotransferase; AST ¼ aspartate aminotransferase; ConA ¼ concanavalin A; DSS ¼ dextran sulfate sodium; IFN-γ ¼ interferon-γ; IL ¼ interleukin; NF-κB ¼ nuclear factor–κB; TGF-β1 ¼ transforming growth factor-β1; VEGF ¼ vascular endothelial growth factor; WT ¼ wild type.

donovani was enhanced by IL-33 administration by blocking TH1 cytokines and liver infiltration of leukocytes.84 Finally, IL-33 augmented pain sensation or nociception in mice challenged with formalin85 and blocking of ST2 receptor alleviated the pain sensation.

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In summary, IL-33 produced disease exacerbating effects mainly by increasing TH2 cytokines, IgE and eosinophilic immune responses, and inhibition of leukocyte recruitment in respiratory, allergic, parasitic, and inflammatory diseases. The sensitizing effects of

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M.I. Arshad et al. IL-33 were found in TH2-prone conditions; therefore, antagonistic IL-33 approaches may prove helpful to mitigate such diseases or inflammatory conditions.

CONCLUSION Although most of the previous studies used an active form of recombinant IL-33, considerations should be taken for dose, route, duration, half-life, pharmacokinetic properties, presence of IL-33 cleaving enzymes, and soluble ST2 to completely comprehend the dual biological activity of IL-33 and rational therapeutic use of IL-33 in various diseases. Because most of the above mentioned effects of IL-33 have been reported in murine disease models, there are some limitations in extrapolation of murine data to humans.

ACKNOWLEDGMENT This work was supported by Inserm, the Ministère de l’Education Nationale de la Recherche et de la Technologie, the University of Rennes 1, and the Région Bretagne. Dr Arshad is supported by research grant 20-4613/NRPU/R&D/HEC/14/45 on hepatoprotective role of IL-33 funded by the Higher Education Commission under the National Research Programme for Universities (NRPU) scheme at University of Agriculture, Faisalabad, Pakistan.

CONFLICTS OF INTEREST The authors have indicated that they have no conflicts of interest regarding the content of this article.

SUPPLEMENTARY MATERIALS Supplementary material cited in this article is available online at http://dx.doi.org/10.1016/j.clinthera.2016. 02.021.

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Address correspondence to: Michel Samson, PhD, INSERM-U1085, IRSET, Université de Rennes 1, 2 Avenue du Professeur Léon Bernard, 35043 Rennes Cedex, France.. E-mail: [email protected]

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GLOSSARY OF ABBREVIATIONS AP-1: Activator protein-1 AHR: Airway hyper responsiveness AREG: Amphiregulin AST: Aspartate aminotransferase ALT: Alanine aminotransferase BALF: Broncho alveolar lavage fluid ConA: Concanavalin A CLP: Cecal ligation puncture CTLs: Cytotoxic T-cells DSS: Dextran sulphate sodium HMGB1: High-mobility group box 1 HSPs: Heat shock proteins HDM: House dust mite HPV: Human papilloma virus IL-33: Interleukin-33 IL-1RAcP: Interleukin-1 receptor accessory protein IRAK: Inteleukin-1 receptor (IL-1R) associated kinase

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ILCs: Innate lymphoid cells I/R: Ischemia-reperfusion TRAF6: Tumor necrosis factor receptor (TNFR) associated factor-6 LCMV: Lymphocytic chorio-meningitis virus LLC: Lewis lung carcinoma MAPK: Mitogen activated protein kinase MPO: Myeloperoxidase MRSA: Methicillin resistant Staphylococcus aureus MyD88: Myeloid differentiation primary response protein 88 NF-HEV: Nuclear factor of high endothelial venules NF-κB: Nuclear factor- κB OVA: Ovalbumin ROS: Reactive oxygen species RSV: Respiratory syncytial virus SLE: Systemic lupus erythematosus

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