We are investigating the role of Th2-type cytokines (IL-4, IL-5, IL-13) in several models of fibrosis that affect the lung, liver, and intestine to determine whether there are common as well as distinct mechanisms of fibrosis in various organ systems and/or fibrotic diseases. Several distinct in vivo models of organ fibrosis are employed, including mouse models of chronic asthma, inflammatory bowel disease, and obesity induced steatosis. Progress was made in following areas over the past year. 1. Role of IL-21 in asthma revealed. Interleukin-21 (IL-21) has been implicated in the development of Th2-mediated immune responses;however, the exact role it plays in allergic diseases is not well understood. To elucidate the contribution of IL-21 receptor signaling to Th2-dependent immune responses in the lung, in collaboration with Dr. Marsha Wills-Karp, we compared allergic airway responses in wild-type BALB/c and Il21r-deficient mice exposed to local airway challenge with house dust mite (HDM). We demonstrated that IL-21R-deficiency reduces HDM-driven airway hyperresponsiveness (AHR) with only partial effects on airway inflammation. Concomitant with the reduction in AHR in Il21r-deficient mice, significant suppression was observed in protein levels of the Th2 cytokines IL-4, and IL-13. In contrast, IL-21R-deficiency was associated with an increase in PBS- and allergen-driven IgE levels, while IgG1 and IgG2a levels were decreased. These results suggest that IL-21 contributes to AHR through its ability to both directly induce Th2 cell survival and to impair regulatory T-cell suppression of Th2 cytokine production. Importantly, we also showed that IL-21-positive cells are increased in the bronchial mucosa of asthmatics compared with non-asthmatics. Together these results suggest that IL-21 plays an important role in the allergic diathesis by enhancing Th2 cytokine production through multiple mechanisms including the suppression of Treg inhibitory effects on Th2 cell cytokine production. 2. IL-1 alpha was identified as a critical activator of human lung fibroblasts. Activation of the innate immune system plays a key role in exacerbations of chronic lung disease, yet the potential role of lung fibroblasts in innate immunity and the identity of epithelial danger signals (alarmins) that may contribute to this process are unclear. The objective of the study was to identify lung epithelial-derived alarmins released during endoplasmic reticulum stress (ER stress) and oxidative stress and evaluate their potential to induce innate immune responses in lung fibroblasts. We found that treatment of primary human lung fibroblasts (PHLFs) with conditioned media from damaged lung epithelial cells significantly upregulated interleukin IL-6, IL-8, monocyte chemotactic protein-1, and granulocyte macrophage colony-stimulating factor expression (P<0.05). This effect was reduced with anti-IL-1αor IL-1Ra but not anti-IL-1βantibody. Costimulation with a Toll-like receptor 3 ligand, polyinosinic-polycytidylic acid (poly I:C), significantly accentuated the IL-1α-induced inflammatory phenotype in PHLFs, and this effect was blocked with inhibitor of nuclear factor kappa-B kinase subunit beta and TGFβ-activated kinase-1 inhibitors. Finally, Il1r1-/- and Il1a-/- mice exhibit reduced bronchoalveolar lavage (BAL) neutrophilia and collagen deposition in response to bleomycin treatment. We conclude that IL-1αplays a pivotal role in triggering proinflammatory responses in fibroblasts and this process is accentuated in the presence of double-stranded RNA. This mechanism may be important in the repeated cycles of injury and exacerbation in chronic lung disease. 3. TNF-alpha/IL-17 were shown to synergistically inhibit the biological activity of IL-13 by up regulating the IL-13 decoy receptor. In this study, we showed that the inflammatory cytokines TNF-a and IL-17, often associated with severe asthma, synergize to induce IL-13Ra2 in primary human lung fibroblasts and mouse lungs. Using a novel IL-13Ra2blocking antibody we also confirmed that Il-13Ra2 primarily functions as a decoy receptor. 4. In collaboration with Dr. Richard Siegel, we found that tumor necrosis factor (TNF)-family cytokine TL1A (TNFSF15) costimulates T cells and promotes diverse T cell-dependent models of autoimmune disease through its receptor DR3. TL1A polymorphisms also confer susceptibility to inflammatory bowel disease. Here, we find that allergic pathology driven by constitutive TL1A expression depends on interleukin-13 (IL-13), but not on T, NKT, mast cells, or commensal intestinal flora. Group 2 innate lymphoid cells (ILC2) express surface DR3 and produce IL-13 and other type 2 cytokines in response to TL1A. DR3 is required for ILC2 expansion and function in the setting of T cell-dependent and -independent models of allergic disease. By contrast, DR3-deficient ILC2 can still differentiate, expand, and produce IL-13 when stimulated by IL-25 or IL-33, and mediate expulsion of intestinal helminths. These data identify costimulation of ILC2 as a novel function of TL1A important for allergic lung disease, and suggest that TL1A may be a therapeutic target in these settings. Other projects initiated over the past year: 1. Transgenic and knockout mice are being used to explore the mechanisms of fibrosis in models of DSS-induced colitis 2. Studies are underway to explore the role of IL-13Ra2 in models of fibrosis and chronic IBD. 3. Studies are underway to better understand the role of the immune system in the development of non-alcoholic fatty liver disease (NAFLD).

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2014
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Gieseck 3rd, Richard L; Wilson, Mark S; Wynn, Thomas A (2018) Type 2 immunity in tissue repair and fibrosis. Nat Rev Immunol 18:62-76
Vannella, Kevin M; Wynn, Thomas A (2017) Mechanisms of Organ Injury and Repair by Macrophages. Annu Rev Physiol 79:593-617
Singh, Brijendra; Kasam, Rajesh K; Sontake, Vishwaraj et al. (2017) Repetitive intradermal bleomycin injections evoke T-helper cell 2 cytokine-driven pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 313:L796-L806
Eming, Sabine A; Wynn, Thomas A; Martin, Paul (2017) Inflammation and metabolism in tissue repair and regeneration. Science 356:1026-1030
Hart, Kevin M; Choy, David F; Bradding, Peter et al. (2017) Accurately measuring and modeling Th2 and Th17 endotypes in severe asthma. Ann Transl Med 5:91
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:
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
Psachoulia, Konstantina; Chamberlain, Kelly A; Heo, Dongeun et al. (2016) IL4I1 augments CNS remyelination and axonal protection by modulating T cell driven inflammation. Brain 139:3121-3136

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