IL‐33 attenuates the development of experimental autoimmune uveitis

Interleukin‐33 (IL‐33) is associated with several important immune‐mediated disorders. However, its role in uveitis, an important eye inflammatory disease, is unknown. Here, we investigated the function of IL‐33 in the development of experimental autoimmune uveitis (EAU). IL‐33 and IL‐33 receptor (ST2) were expressed in murine retinal pigment epithelial (RPE) cells in culture, and IL‐33 increased the expression of Il33 and Mcp1 mRNA in RPE cells. In situ, IL‐33 was highly expressed in the inner nuclear cells of the retina of naïve mice, and its expression was elevated in EAU mice. ST2‐deficient mice developed exacerbated EAU compared with WT mice, and administration of IL‐33 to WT mice significantly reduced EAU severity. The attenuated EAU in IL‐33‐treated mice was accompanied by decreased frequency of IFN‐γ⁺ and IL‐17⁺ CD4⁺ T cells and reduced IFN‐γ and IL‐17 production but with increased frequency of IL‐5⁺ and IL‐4⁺ CD4 T cells and IL‐5 production in the draining lymph node and spleen. Macrophages from the IL‐33‐treated mice show a significantly higher polarization toward an alternatively activated macrophage phenotype. Our results therefore demonstrate that the endogenous IL‐33/ST2 pathway plays an important role in EAU, and suggest that IL‐33 represents a potential option for treatment of uveitis.     

Interleukin‐6 blockade in ocular inflammatory diseases

Interleukin‐6 (IL‐6) is a key cytokine featuring redundancy and pleiotropic activity. It plays a central role in host defence against environmental stress such as infection and injury. Dysregulated, persistent interleukin (IL)‐6 production has been implicated in the development of various autoimmune, chronic inflammatory diseases and even cancers. Significant elevation of IL‐6 has been found in ocular fluids derived from refractory/chronic uveitis patients. In experimental autoimmune uveitis models with IL‐6 knock‐out mice, IL‐6 has shown to be essential for inducing inflammation. IL‐6 blockade can suppress acute T helper type 17 (Th17) responses via its differentiation and, importantly, can ameliorate chronic inflammation. Tocilizumab, a recombinant humanized anti‐IL‐6 receptor antibody, has been shown to be effective in several autoimmune diseases, including uveitis. Herein, we discuss the basic biology of IL‐6 and its role in development of autoimmune conditions, focusing particularly on non‐infectious uveitis. It also provides an overview of efficacy and safety of tocilizumab therapy for ocular inflammatory diseases.     

IL‐33 citrine reporter mice reveal the temporal and spatial expression of IL‐33 during allergic lung inflammation

Interleukin‐33 (IL‐33) is an IL‐1 family cytokine that signals via its receptor T1/ST2, and is a key regulator of inflammation, notably the type‐2 response implicated in allergic asthma. Critical to our understanding of the role of IL‐33 is the identification of the cellular sources of IL‐33. Although progress has been made in this area, the development of a robust live cell reporter of expression would allow the localisation of IL‐33 during ongoing immune responses. We have generated a fluorescent reporter mouse line, Il33^Cit/+, to define the expression profile of IL‐33 in vivo and demonstrate its temporal and spatial expression during experimental allergic asthma responses. We found that type‐2 pneumocytes constitute the major source of IL‐33 upon allergic lung inflammation following exposure to OVA, fungal extract or ragweed pollen. Using Il33^Cit/Cit mice (IL‐33‐deficient), we establish a role for IL‐33 early in the initiation of type‐2 responses and the induction of nuocytes (ILC2). We also demonstrate a potential mechanism of action by which IL‐33 rapidly initiates type‐2 immune responses. Il33^Cit/+ mice have enabled new insights into the initiation of type‐2 responses and will provide an important tool for further dissection of this important inflammatory pathway in vivo.     

Functions of interleukin‐34 and its emerging association with rheumatoid arthritis

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic, synovial inflammation affecting multiple joints, finally leading to extra‐articular lesions for which limited effective treatment options are currently available. Interleukin‐34 (IL‐34), recently discovered as the second colony‐stimulating factor‐1 receptor (CSF‐1R) ligand, is a newly discovered cytokine. Accumulating evidence has disclosed crucial roles of IL‐34 in the proliferation and differentiation of mononuclear phagocyte lineage cells, osteoclastogenesis and inflammation. Recently, IL‐34 was detected at high levels in patients with active RA and in experimental models of inflammatory arthritis. Blockade of functional IL‐34 with a specific monoclonal antibody can reduce the severity of inflammatory arthritis, suggesting that targeting IL‐34 or its receptors may constitute a novel therapeutic strategy for autoimmune diseases such as RA. Here, we have comprehensively discussed the structure and biological functions of IL‐34, and reviewed recent advances in our understanding of the emerging role of IL‐34 in the development of RA as well as its potential utility as a therapeutic target.     

IL‐23 in the Pathogenesis of Rheumatoid Arthritis

Interleukin‐23 (IL‐23) is a heterodimeric cytokine belonging to the IL‐6/IL‐12 family that plays a key role in several of autoimmune and inflammatory disorders. This family contains the 34 type I cytokine receptor chains and 27 ligands, which share structural and functional similarities, but on the other hand they display distinct roles in shaping Th cells responses. IL‐12 family cytokines have not only proinflammatory effects but they also promote inflammatory responses. IL‐23 is composed of the p40 subunit in common with IL‐12, and with a unique p19 subunit. IL‐23 binding to an IL‐23 receptor expressed on dendritic cells, macrophages and monocytes triggers the activation of Jak2 and Tyk2, which in turn phosphorylates STAT1, STAT3, STAT4 and STAT5 as well as induce formation of STAT3‐STAT4 heterodimers. IL‐23 is one of the essential factors required for the survival and/or expansion of Th17 cells, which produce IL‐17, IL‐17F, IL‐6 and TNF‐α. Th17 cells stimulated by the IL‐23 promote osteoclastogenesis through production of IL‐17, which induce receptor activator of NF‐kappa B ligand on mesenchymal cells. The IL‐23‐IL‐17 axis includes Th17 cells and plays a key role in the development of autoimmune arthritis.     

Interleukin 33: an innate alarm for adaptive responses beyond Th2 immunity–emerging roles in obesity,intestinal inflammation,and cancer

Interleukin (IL)‐33, a member of the IL‐1 family, was originally described in 2005 as a potent initiator of type 2 immunity found during allergic inflammation and parasitic infections. IL‐33 has been shown to play important and potent roles bridging innate and adaptive immunity in the regulation of tissue homeostasis, injury, and repair. Recent discoveries have extended the range of functions for IL‐33 beyond type 2 conditions and its role as an alarmin at barrier sites, with emerging central roles for IL‐33 in T‐cell regulation, obesity, viral and tumor immunity. Here, we review the recent advances on how IL‐33 activity is regulated, its immunomodulatory properties on innate and adaptive cells, and the newly discovered roles of IL‐33 in obesity, intestinal inflammation, and tumorigenesis.     

Expression and regulation of interleukin-33 in human monocytes

Interleukin‐33 (IL‐33) is an IL‐1 family cytokine that has a role in regulating T helper type 2 cytokines and mast cell development. Expression of IL‐33 is also associated with chronic inflammatory conditions such as rheumatoid arthritis. However, there is little information regarding IL‐33 in myeloid cell immune responses, which are important in immunity and inflammation. We therefore investigated the expression, intracellular location and regulation of myeloid cell IL‐33 by lipopolysaccharide (LPS) from Escherichia coli and the periodontal pathogen Porphyromonas gingivalis. We detected IL‐33 messenger RNA in the human promonocytic cell line THP‐1, in monocytes derived from these cells and in primary human monocytes. However, IL‐33 was not expressed in primary monocyte‐derived dendritic cells. Stimulation of monocytes with E. coli LPS (Toll‐like receptor 4 agonist) and LPS from P. gingivalis (Toll‐like receptor 2 agonist) up‐regulated IL‐33 at both the messenger RNA and protein levels but IL‐1β and tumour necrosis factor‐α had no effect. The IL‐33 protein was mainly found in the cytoplasm of monocytes with no evidence of nuclear translocation in stimulated cells. Furthermore, no IL‐33 secretion was detected after stimulation with LPS and/or ATP. These data indicate that the function, if any, of IL‐33 in activated monocytes is primarily intracellular. Interestingly, immunofluorescence analysis indicated that IL‐33 was sequestered in the nucleus of monocytes undergoing apoptosis but released into the extracellular milieu by LPS‐stimulated cells in which necrosis had been induced by freeze–thawing. Therefore, this endorses the view that IL‐33 may function as an ‘alarmin’ and have a role in signalling cellular damage and inflammatory disease pathogenesis through release from damaged or necrotic cells.     

IL‐17 Induces Expression of Vascular Cell Adhesion Molecule Through Signalling Pathway of NF‐κB,but not Akt1 and TAK1 in Vascular Smooth Muscle Cells

Interleukin‐17 (IL‐17) plays an important role in several autoimmune diseases. IL‐17 can induce the expression of vascular cell adhesion molecule (VCAM‐1) in aortic vascular smooth muscle cells (SMCs), which is important for the development of atherosclerosis. However, the signalling pathway of IL‐17‐induced VCAM‐1 expression remains unclear. In this study, we reported that IL‐17‐induced expression of VCAM‐1 in SMCs is dependent on NF‐κB, but independent of Akt1 and TAK1. This is because knocking down Akt1 or TAK1 by siRNA did not reduce IL‐17‐induced activation of NF‐κB and expression of VCAM‐1, whereas knocking down NF‐κB by siRNA markedly inhibited IL‐17‐mediated upregulation of VCAM‐1 expression. In addition, IL‐17‐induced expression of VCAM‐1 is partially dependent on activation of ERK1/2. Therefore, these signalling pathways of IL‐17‐mediated upregulation of VCAM‐1 expression might be therapeutic targets for treatment of IL‐17‐mediated inflammation.     

Anti‐interleukin‐33 inhibits cigarette smoke‐induced lung inflammation in mice

The mechanism by which cigarette smoke (CS) causes chronic obstructive pulmonary disease (COPD) is poorly understood. Interleukin‐33 (IL‐33) is a pleiotropic cytokine predominantly expressed in lung tissue and can elicit airway inflammation in naive mice. We tested the hypothesis that IL‐33 is induced by CS and contributes to CS‐mediated airway inflammation in a mouse model of CS‐induced COPD. Groups of mice were exposed to CS three times per day for 4 consecutive days. The expression levels of IL‐33 and ST2 were markedly enhanced in the lung tissue of mice inhaling CS. Exposure to CS also induced neutrophil and macrophage infiltration and expression of inflammatory cytokines (IL‐1β, tumour necrosis factor‐α, IL‐17), chemokines (monocyte chemoattractant protein‐1) and mucin 5, subtypes A and C in the airways. More importantly, all of these CS‐induced pathogenic changes were significantly inhibited by treatment with neutralizing anti‐IL‐33 antibody delivered intranasally. Hence, our results suggest that IL‐33 plays a critical role in CS‐mediated airway inflammation and may be a therapeutic target in CS‐related diseases, including COPD.     

Distinct sustained structural and functional effects of interleukin‐33 and interleukin‐25 on the airways in a murine asthma surrogate

Interleukin‐25 (IL‐25) and IL‐33, which belong to distinct cytokine families, induce and promote T helper type 2 airway inflammation. Both cytokines probably play a role in asthma, but there is a lack of direct evidence to clarify distinctions between their functions and how they might contribute to distinct ‘endotypes’ of disease. To address this, we made a direct comparison of the effects of IL‐25 and IL‐33 on airway inflammation and physiology in our established murine asthma surrogate, which involves per‐nasal, direct airway challenge. Intranasal challenge with IL‐33 or IL‐25 induced inflammatory cellular infiltration, collagen deposition, airway smooth muscle hypertrophy, angiogenesis and airway hyper‐responsiveness, but neither increased systemic production of IgE or IgG1. Compared with that of IL‐25, the IL‐33‐induced response was characterized by more sustained laying down of extracellular matrix protein, neoangiogenesis, T helper type 2 cytokine expression and elevation of tissue damping. Hence, both IL‐25 and IL‐33 may contribute significantly and independently to asthma ‘endotypes’ when considering molecular targets for the treatment of human disease.     

IL-33 attenuates EAE by suppressing IL-17 and IFN-γ production and inducing alternatively activated macrophages

Interleukin (IL)-33, a member of the IL-1 cytokine family, is an important modulator of the immune system associated with several immune-mediated disorders. High levels of IL-33 are expressed by the central nervous system (CNS) suggesting a potential role of IL-33 in autoimmune CNS diseases. We have investigated the expression and function of IL-33 in the development of experimental autoimmune encephalomyelitis (EAE) in mice. We report here that IL-33 and its receptor ST2 (IL-33Rα) are highly expressed in spinal cord tissue, and ST2 expression is markedly increased in the spinal cords of mice with EAE. Furthermore, ST2-deficient (ST2(-/-) ) mice developed exacerbated EAE compared with wild-type (WT) mice while WT, but not ST2(-/-) EAE mice treated with IL-33 developed significantly attenuated disease. IL-33-treated mice had reduced levels of IL-17 and IFN-γ but produced increased amounts of IL-5 and IL-13. Lymph node and splenic macrophages of IL-33-treated mice showed polarization toward an alternatively activated macrophage (M2) phenotype with significantly increased frequency of MR(+) PD-L2(+) cells. Importantly, adoptive transfer of these IL-33-treated macrophages attenuated EAE development. Our data therefore demonstrate that IL-33 plays a therapeutic role in autoimmune CNS disease by switching a predominantly pathogenic Th17/Th1 response to Th2 activity, and by polarization of anti-inflammatory M2 macrophages.     

Interleukin‐9 and T helper type 9 cells in rheumatic diseases

Interleukin (IL)‐9 is a 28‐30 kDa monomeric glycosylated polypeptide belonging to the IL‐7/IL‐9 family of proteins that bind to a composite receptor consisting of the private receptor IL‐9R and the IL‐2 receptor, gamma (IL‐2RG), a common gamma subunit shared by the receptors of many different cytokines. The IL‐9R is expressed widely and IL‐9 impacts a number of effector cells, such as effector T cells, B cells, innate lymphoid cells, mast cells, polymorphonuclear cells, epithelial cells and smooth muscle cells, playing an important role in regulating inflammatory immunity. The critical role of IL‐9 in promoting cellular and humoral immune responses makes it an important focus of potential therapeutic interventions. Recently, a defined subset of T helper type cells, Th9 cells, has been identified by the potent production of IL‐9. The involvement of the Th9 cell subset has been described in many types of inflammatory diseases, namely atopic diseases, helminth infections, experimental autoimmune encephalomyelitis and ulcerative colitis. In this review, we summarize the IL‐9 biological activities, highlighting roles for IL‐9 and Th9 cells in rheumatoid and psoriatic arthritis, systemic vasculitis, systemic lupus erythematosus and systemic sclerosis.     

The role of IL‐23 receptor signaling in inflammation‐mediated erosive autoimmune arthritis and bone remodeling

The IL‐23/Th17 axis has been implicated in the development of autoimmune diseases, such as rheumatoid arthritis (RA) and psoriatic arthritis (PsA). RA and PsA are heterogeneous diseases with substantial burden on patients. Increasing evidence suggests that the IL‐23 signaling pathway may be involved in the development of autoimmunity and erosive joint damage. IL‐23 can act either directly or indirectly on bone forming osteoblasts as well as on bone resorbing osteoclasts. As IL‐23 regulates the activity of cells of the bone, it is conceivable that in addition to inflammation‐mediated joint erosion, IL‐23 may play a role in physiological bone remodeling. In this review, we focus on the role of IL‐23 in autoimmune arthritis in patients and murine models, and provide an overview of IL‐23 producing and responding cells in autoimmune arthritic joints. In addition, we discuss the role of IL‐23 on bone forming osteoblasts and bone resorbing osteoclasts regarding inflammation‐mediated joint damage and bone remodeling. At last, we briefly discuss the clinical implications of targeting this pathway for joint damage and systemic bone loss in autoimmune arthritis.     

Functional interleukin‐33 receptors are expressed in early progenitor stages of allergy‐related granulocytes

Interleukin‐33 (IL‐33) induces T helper type 2 (Th2) cytokine production and eosinophilia independently of acquired immunity, leading to innate immunity‐mediated allergic inflammation. Allergy‐related innate myeloid cells such as eosinophils, basophils and mast cells express the IL‐33 receptor (IL‐33R), but it is still unknown how IL‐33 regulates allergic inflammation involving these cells and their progenitors. Here, we revealed that the functional IL‐33R was expressed on eosinophil progenitors (EoPs), basophil progenitors (BaPs) and mast cell progenitors (MCPs). In the presence of IL‐33, these progenitors did not expand, but produced a high amount of Th2 and pro‐inflammatory cytokines such as IL‐9, IL‐13, IL‐1β and IL‐6. The amount of cytokines produced by these progenitors was greater than that by mature cells. In vivo, IL‐33 stimulated the expansion of EoPs, but it was dependent upon the elevated serum IL‐5 that is presumably derived from type 2 innate lymphoid cells that express functional IL‐33R. These data collectively suggest that EoPs, BaPs and MCPs are not only the sources of allergy‐related granulocytes, but can also be sources of allergy‐related cytokines in IL‐33‐induced inflammation. Because such progenitors can differentiate into mature granulocytes at the site of inflammation, they are potential therapeutic targets in IL‐33‐related allergic diseases.     

IL‐6: Regulator of Treg/Th17 balance

IL‐6 is a pleiotropic cytokine involved in the physiology of virtually every organ system. Recent studies have demonstrated that IL‐6 has a very important role in regulating the balance between IL‐17‐producing Th17 cells and regulatory T cells (Treg). The two T‐cell subsets play prominent roles in immune functions: Th17 cell is a key player in the pathogenesis of autoimmune diseases and protection against bacterial infections, while Treg functions to restrain excessive effector T‐cell responses. IL‐6 induces the development of Th17 cells from naïve T cells together with TGF‐β; in contrast, IL‐6 inhibits TGF‐β‐induced Treg differentiation. Dysregulation or overproduction of IL‐6 leads to autoimmune diseases such as multiple sclerosis (MS) and rheumatoid arthritis (RA), in which Th17 cells are considered to be the primary cause of pathology. Given the critical role of IL‐6 in altering the balance between Treg and Th17 cells, controlling IL‐6 activities is potentially an effective approach in the treatment of various autoimmune and inflammatory diseases. Here, we review the role of IL‐6 in regulating Th17/Treg balance and describe the critical functions of IL‐6 and Th17 in immunity and immune‐pathology.     

Interleukin‐33 exacerbates acute colitis via interleukin‐4 in mice

Interleukin‐33 (IL‐33) and its receptor ST2 are over‐expressed in clinical colitis tissue. However, the significance of these observations is at present unknown. Significantly, we demonstrate here that IL33 and ST2 are the primary early genes induced in the inflamed colon of BALB/c mice following dextran sulphate sodium (DSS)‐induced experimental ulcerative colitis. Accordingly diarrhoea and DSS‐induced colon inflammation were impaired in ST2^?/? BALB/c mice and exacerbated in wild‐type mice by treatment with exogenous recombinant IL‐33, associated respectively with reduced and enhanced expression of chemokines (CXCL9 and CXCL10), and inflammatory (IL‐4, IL‐13, IL‐1, IL‐6, IL‐17) and angiogenic (vascular endothelial growth factor) cytokines in vivo. The exacerbation effect of treatment with recombinant IL‐33 on DSS‐induced acute colitis was abolished in IL‐4^?/? BALB/c mice. Hence, IL‐33 signalling via ST2, by inducing an IL‐4‐dependent immune response, may be a major pathogenic factor in the exacerbation of ulcerative colitis.     

IL‐21 and autoimmune disease – hypothesis and reality?

Previous data have indicated that IL‐21 and/or IL‐21R are crucial for the differentiation of naïve T cells into Th17 cells and also play a key role in the development of autoimmune disease. Given this, IL‐21 and/or IL‐21R are potential targets for therapy of such diseases; however, a study in this issue of the European Journal of Immunology, provides a new twist in the story as it is now shown that IL‐21 and/or IL‐21R play no role in Th17 development or autoimmune inflammatory disease. The reasons for these contradictory data are discussed in this Commentary. See accompanying article: http://dx.doi.org/10.1002/eji.200838511