Welcome to the neighborhood: epithelial cell‐derived cytokines license innate and adaptive immune responses at mucosal sites

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IL-33 is a novel member of the IL-1 family and ligand for the IL-1 receptor-related protein, ST2. Recent evidence suggests that the IL-33/ST2 axis plays a critical role in several autoimmune and inflammatory disorders; however, its role in inflammatory bowel disease (IBD) has not been clearly defined. We characterized IL-33 and ST2 expression and modulation after conventional anti-TNF therapy in Crohn's disease and ulcerative colitis (UC) patients and investigated the role of IL-33 in SAMP1/YitFc (SAMP) mice, a mixed Th1/Th2 model of IBD. Our results showed a specific increase of mucosal IL-33 in active UC, localized primarily to intestinal epithelial cells (IEC) and colonic inflammatory infiltrates. Importantly, increased expression of full-length IL-33, representing the most bioactive form, was detected in UC epithelium, whereas elevated levels of cleaved IL-33 were present in IBD serum. ST2 isoforms were differentially modulated in UC epithelium, and sST2, a soluble decoy receptor with anti-inflammatory properties, was also elevated in IBD serum. Infliximab (anti-TNF) treatment of UC decreased circulating IL-33 and increased sST2, whereas stimulation of HT-29 IEC confirmed IL-33 and sST2 regulation by TNF. Similarly, IL-33 significantly increased and correlated with disease severity, and potently induced IL-5, IL-6, and IL-17 from mucosal immune cells in SAMP mice. Taken together, the IL-33/ST2 system plays an important role in IBD and experimental colitis, is modulated by anti-TNF therapy, and may represent a specific biomarker for active UC.inflammatory bowel disease | anti-TNF therapy | SAMP1/YitFc mouse model

Section: Discussionmentioning

confidence: 99%

Epithelial-derived IL-33 and its receptor ST2 are dysregulated in ulcerative colitis and in experimental Th1/Th2 driven enteritis

Pastorelli

Garg

Hoang

et al. 2010

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395

“…More recently, the cytokines IL-25 and IL-33, members of the IL-17 and IL-1 cytokine families, respectively, were found to induce type 2 cytokine production when administered to mice, implicating these cytokines in the initiation of type 2 immune responses (6,7). IL-25 and IL-33 are expressed by epithelial cells, macrophages, and possibly other cell types (8), and they are expressed at elevated levels during infection with parasitic helminths (9,10) or after challenge with allergens (9,11). Administration of exogenous IL-25 or IL-33 to mice leads to markedly enhanced levels of IL-4, IL-5, and IL-13 and many of the tissue features of a type 2 immune response (6,7).…”

mentioning

confidence: 99%

Systemically dispersed innate IL-13–expressing cells in type 2 immunity

Price

Liang

Sullivan

et al. 2010

1,004

1,147

Type 2 immunity is a stereotyped host response to allergens and parasitic helminths that is sustained in large part by the cytokines IL-4 and IL-13. Recent advances have called attention to the contributions by innate cells in initiating adaptive immunity, including a novel lineage-negative population of cells that secretes IL-13 and IL-5 in response to the epithelial cytokines IL-25 and IL-33. Here, we use IL-4 and IL-13 reporter mice to track lineage-negative innate cells that arise during type 2 immunity or in response to IL-25 and IL-33 in vivo. Unexpectedly, lineage-negative IL-25 (and IL-33) responsive cells are widely distributed in tissues of the mouse and are particularly prevalent in mesenteric lymph nodes, spleen, and liver. These cells expand robustly in response to exogenous IL-25 or IL-33 and after infection with the helminth Nippostrongylus brasiliensis, and they are the major innate IL-13-expressing cells under these conditions. Activation of these cells using IL-25 is sufficient for worm clearance, even in the absence of adaptive immunity. Widely dispersed innate type 2 helper cells, which we designate Ih2 cells, play an integral role in type 2 immune responses.T ype 2 immune responses are important for the control of infections at mucosal barriers and the development of allergic inflammation. These responses are characterized by eosinophilia, elevated IgE, goblet cell metaplasia with enhanced mucus production, and smooth muscle hyperreactivity, all of which rely critically on production of the canonical type 2-associated cytokines IL-4, IL-5, and IL-13 (1, 2). Although adaptive Th2 cells and follicular T cells are important sources of these cytokines (3), various innate cells, including eosinophils, basophils, and mast cells, have also been implicated as producers of these cytokines in various model systems (1, 2, 4, 5). More recently, the cytokines IL-25 and IL-33, members of the IL-17 and IL-1 cytokine families, respectively, were found to induce type 2 cytokine production when administered to mice, implicating these cytokines in the initiation of type 2 immune responses (6, 7). IL-25 and IL-33 are expressed by epithelial cells, macrophages, and possibly other cell types (8), and they are expressed at elevated levels during infection with parasitic helminths (9, 10) or after challenge with allergens (9, 11). Administration of exogenous IL-25 or IL-33 to mice leads to markedly enhanced levels of IL-4, IL-5, and IL-13 and many of the tissue features of a type 2 immune response (6, 7). Conversely, deficiency in IL-25 leads to diminished IL-4, IL-5, and IL-13 production and variable delays in worm clearance in different helminth models (12, 13). Similarly, mice unable to respond to IL-33 because of deficiency in the T1-ST2 subunit of the IL-33 receptor display diminished Th2-associated cytokines and decreased granuloma formation after injection of Schistosoma mansoni eggs (14).Some of the original descriptions of these cytokines as well as more recent reports have noted the capacity of exogenous ...

“…A member of the IL-1 family, IL-33 is expressed primarily by stromal cells, such as epithelial cells, endothelial cells, and fibroblasts, as well as by certain hematopoietic cells, including MC themselves (24)(25)(26). IL-33 is an "alarmin" released upon cell necrosis and also can be secreted by live cells after mechanical stretching and via other incompletely defined mechanisms (27,28).…”

mentioning

confidence: 99%

IL-33/ST2 axis promotes mast cell survival via BCLXL

Wang

Kaieda

Ameri

et al. 2014

Mast cells (MC) are potent innate immune cells that accumulate in chronically inflamed tissues. MC express the IL-33 receptor IL-1 receptor-related protein ST2 at high level, and this IL-1 family cytokine both activates MC directly and primes them to respond to other proinflammatory signals. Whether IL-33 and ST2 play a role in MC survival remains to be defined. In skin-derived human MC, we found that IL-33 attenuated MC apoptosis without altering proliferation, an effect mediated principally through the antiapoptotic molecule B-cell lymphoma-X large (BCLXL). Murine MC demonstrated a similar mechanism, dependent entirely on ST2. In line with these observations, St2−/− mice exhibited reduced numbers of tissue MC in inflamed arthritic joints, in helminthinfected intestine, and in normal peritoneum. Together, these data reveal a cell-intrinsic role for the IL-33/ST2 axis in the regulation of apoptosis in MC, identifying thereby a previously unappreciated pathway supporting expansion of the MC population with inflammation.arthritis | helminth infection M ast cells (MC) are tissue-resident effector cells that contribute both to innate and adaptive immunity (1). MC help defend against bacterial and helminthic infection (2, 3) and play a role in tissue remodeling (4, 5). MC can also contribute to a variety of allergic and nonallergic inflammatory diseases, such as anaphylaxis, atopic dermatitis, asthma, inflammatory arthritis, psoriasis, and multiple sclerosis (6, 7). Under many of these conditions, the number of MC in affected tissues increases by tenfold or more, amplifying the contribution of MC-derived mediators to ongoing inflammation (6-8). Regulation of the MC population is poorly understood, and therapeutic intervention to limit MC accumulation potentially could attenuate injury associated with inflammatory diseases (9, 10).The survival of mature MC in tissues depends on signals from neighboring cells (11,12). The single most important mediator in this process is stem cell factor (SCF), a master regulator of MC proliferation, differentiation, survival, and activation. Mice with genetic mutations affecting SCF or its receptor Kit have few or no MC in healthy or inflamed tissues, whereas activating mutations of Kit give rise to pathologic mastocytosis (13-15). IL-3 is another well-recognized MC growth factor (16). SCF/Kit and IL-3 interface with several antiapoptotic pathways, up-regulating the antiapoptotic protein B-cell lymphoma-2 (BCL-2) and downregulating the proapoptotic protein Bim (14,(17)(18)(19). Aside from SCF/Kit and IL-3, other cytokines have been reported to support MC survival, but their effects appear to be restricted to specific MC subtypes. IL-4 promotes survival of intestinal MC via both BCL-2 and B-cell lymphoma-X large (BCLXL) but may suppress survival in human cord blood MC as well as murine bone marrowderived MC (BMMC) (20-23). IL-10 can either promote or impair survival depending on the type of MC studied (21,22).Recently, substantial attention has focused on the role of IL-33 in MC biolog...