We are investigating the role of Type-2 immunity 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 high fat diet induced steatosis. Progress was made in following areas over the past year: 1. Type 2 immunity is characterized by the production of the cytokines interleukin-4 (IL-4), IL-5, IL-9, and IL-13, which play diverse roles in the immune response. In addition to suppressing the proinflammatory activity of type 1 immune responses, type 2 immunity regulates wound healing, metabolic homeostasis, and immunity to several extracellular parasites. However, although the type 2 response exhibits many host-protective functions, should these responses persist or become dysregulated, they can contribute to the development of disease. Chronic type 2 cytokine production underlies diseases including allergic asthma, atopic dermatitis, allergic rhinitis, ulcerative colitis, and many chronic fibroproliferative disorders. Therefore, a better understanding of the mechanisms that regulate the initiation, maintenance, and resolution of type 2 immune responses could reveal novel approaches to treat a host of important human diseases. Three predominantly epithelial cellderived cytokinesTSLP ( thymic stromal lymphopoietin), IL-25, and IL-33have emerged as important initiators of type 2 immunity in mammals, and their expression during type 2 disease in humans is widely documented. These alarmins are released from the epithelium and other local stromal compartments when cells are damaged or stressed by allergens, pollutants, or pathogens and thereby trigger the production of the canonical type 2 cytokines IL-5, IL-9, and IL-13 by human and mouse cells of the innate and adaptive immune system. TSLP targets dendritic cells (DCs), basophils, mast cells, monocytes, natural killer T cells, and type 2 innate lymphoid cells (ILC2s). In humans, TSLP has been shown to induce nave human CD4+ T helper 2 (TH2) cell responses, but only in the presence of DCs. IL-25 and IL-33 exhibit similar TH2-inducing activity, but rather than targeting DCs, myeloid cells, and TH2 cells, they largely promote type 2 immunity by stimulating ILC2s as well as basophils, mast cells, and eosinophils. IL-33 will amplify antigen-dependent and antigen-independent effector responses from both human and mouse TH2 cells. One recent study revealed that IL-33 could enhance TSLP- and DC-mediated human TH2 memory responses in vitro, suggesting the alarmins could play a role in maintaining immune responses. Although TSLP, IL-25, and IL-33 have all been shown to promote type 2 immunity when overexpressed in mice, the requirement for these cytokines in the development of type 2 immunity in response to allergens and helminth parasites has been more variable, with some studies identifying little to no role for TSLP, IL-25, or IL-33 when targeted individually. This variability has been attributed to the redundant and overlapping functional activities of these cytokines. IL-33 and IL-25 have both been shown to induce production of IL-13 by human ILCs in vitro. However, this theory was not systematically investigated in vivo, nor were the combined roles of the three cytokines dissected in models of chronic type 2dependent disease. Therefore, we used both genetic- and monoclonal antibody (mAb)based strategies to investigate whether bi-functional or tri-functional targeting of TSLP-, IL-25, and IL-33dependent signaling more effectively controls pathogenic TH2 responses than disrupting any of the pathways individually. The roles of the three cytokines in the initiation and maintenance of primary and secondary type 2 immune responses were investigated in both acute and chronic models of lung inflammation and during chronic helminth infection. A major goal was to investigate whether type 2 cytokinedriven inflammation and fibrosis could be ameliorated more effectively if all three epithelial cytokines were targeted in combination. Our studies were also designed to investigate whether TSLP, IL-25, and IL-33, either alone or in combination, are required for the maintenance of established type 2driven disease, because this is the stage where most therapeutic strategies are initiated. The results from these studies revealed partially redundant roles for TSLP, IL-25, and IL-33 in the maintenance of type 2 pathology and suggest that for some diseases, early combined targeting of these mediators is necessary to ameliorate progressive type 2driven disease. 2. Chitin is the second most abundant polymer in nature, found as a structural component in fungi, arthropods, and parasitic nematodes. Mammals do not synthesize chitin, but they express two known enzymes that digest chitin: acidic mammalian chitinase (AMCase) and chitotriosidase. It is known that AMCase is expressed in the lung and the gastrointestinal tract of humans and mice, and that its activity is markedly increased in epithelial cells and macrophages in response to the type 2 cytokines IL-4 and IL-13, yet its role in type 2 inflammation and immunity were unclear. Most studies investigating AMCase function have focused on its role in allergic lung disease. Mice congenitally lacking AMCase (AMCase-deficient) demonstrated little to no role for the enzyme in acute models of house-dust-mite- or ovalbumin (OVA)-induced allergy in the lung. These findings contrasted with those of another published study in which neutralizing AMCase activity with allosamidin or with a monoclonal antibody resulted in marked diminution of IL-13-driven allergic inflammation, suggesting that the enzyme might represent an attractive therapeutic target in allergic asthma. Still, additional reports have proposed that AMCase has a protective role. One showed that the type 2 inflammatory response following chitin challenge was ameliorated in mice overexpressing AMCase, and another observed increased allergic lung disease in mice specifically lacking AMCase enzymatic activity. The contrasting functional implications of AMCase highlighted in these studies have yet to be fully reconciled. Further, allergic inflammation recapitulates the prototypic type 2 response seen after helminth infection, but, surprisingly, despite the discovery that AMCase is highly expressed after exposure to helminths, it has remained unknown whether the enzyme has any role in the host immune response to these important human pathogens. We used AMCase-deficient mice as a means to dissect the role of the enzyme in several models of helminth infection and type 2 cytokinedriven airway inflammation. We showed that although AMCase activity is largely dispensable in the development of allergic airway disease, the enzyme plays a critical role in the development of type 2 immunity to the gastrointestinal nematodes N. brasiliensis and H. p. bakeri.
| 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: |
| 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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