Although IL-13 clearly plays an important role in the schistosomiasis model, it remains unclear to what extent targeting this pathway might be useful in the treatment of other fibroproliferative diseases. Therefore, we have begun to investigate the role of Th2-type cytokines in other models of fibrosis to determine whether there are common as well as distinct mechanisms of fibrosis in various organ systems and/or diseases. The models that were set up in the lab over the past few years include a mouse model of chronic asthma, which is being used to investigate the mechanisms pulmonary remodeling in response to chronic allergen challenge, the bleomycin models of lung and skin fibrosis, and several models if intestinal inflammation. Projects completed during the past year: Crohns disease and ulcerative colitis are believed to be induced by distinct immunologic mechanisms, with mixed Th1/Th17 responses mediating Crohns disease and persistent Th2-type responses triggering ulcerative colitis. In the case of Crohns disease, a variety of mechanisms have been shown to limit the production of interferon (IFN)-g/interleukin (IL)-17A and development of severe disease, including regulatory cell populations, immunoregulatory cytokines, and anti-inflammatory proteins. However, the cytokine IL-10 has emerged as a key suppressive mediator. Indeed, animal studies and genetic linkage association studies have revealed an important protective role for IL-10 in colitis. Although Th2 cytokines, in particular IL-4 and IL-13, can also antagonize Th1/Th17 responses, the mechanisms by which Th2 responses regulate the development of colitis remain much less clear. Using 2 independent models of chemical- and infection-induced intestinal inflammation, we showed that the development of Th1/Th17-dependent disease in il10-/- mice is tightly regulated by the IL-13 decoy receptor (IL-13Ra2). During Trichuris muris infection or following exposure to the nonsteroidal anti-inflammatory drug piroxicam (a gastrointestinal toxin), production of IL-13Ra2 increased in the absence of IL-10, consistent with our previous studies in the lung and liver, resulting in decreased IL-13 bioactivity and markedly increased IFN-g/IL-17A-driven intestinal inflammation. As such, these studies revealed a previously unrecognized role for IL-13 and its decoy receptor in the regulation of Th1/Th17 responses in the gut. Because the IL-13Ra2 chain is primarily expressed on epithelial cells, smooth muscle, and fibroblasts, they also illustrate a novel mechanism for cells of nonhematopoietic origin to control IFN-g/IL-17mediated intestinal inflammation. Finally, using in vitro polarized CD4+ T cells, we confirm that Th17 cells express a functional IL-13 receptor that, when activated with IL-13, can directly reduce the frequency of Th17 cells and secretion of IL-17A, thus providing an additional mechanism for IL-13 to limit Th17-dependent pathology in the gastrointestinal tract.
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| Citrin, Deborah E; Prasanna, Pataje G S; Walker, Amanda J et al. (2017) Radiation-Induced Fibrosis: Mechanisms and Opportunities to Mitigate. Report of an NCI Workshop, September 19, 2016. Radiat Res 188:1-20 |
| Hart, Kevin M; Fabre, Thomas; Sciurba, Joshua C et al. (2017) Type 2 immunity is protective in metabolic disease but exacerbates NAFLD collaboratively with TGF-?. Sci Transl Med 9: |
| Chung, Su I; Horton, Jason A; Ramalingam, Thirumalai R et al. (2016) IL-13 is a therapeutic target in radiation lung injury. Sci Rep 6:39714 |
| Vannella, Kevin M; Ramalingam, Thirumalai R; Hart, Kevin M et al. (2016) Acidic chitinase primes the protective immune response to gastrointestinal nematodes. Nat Immunol 17:538-44 |
| Soucy, Katie; Fairhurst, Rick M; Lynn, Geoffrey M et al. (2016) Breaking the Mold: Partnering with the National Institutes of Health Intramural Research Program to Accelerate PhD Training. Trends Immunol 37:813-815 |
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