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, and the bleomycin models of lung and skin fibrosis.
Projects completed during the past year:
Although a variety of cytokines, chemokines, and growth factors are important regulators of fibrosis, we previously identified a critical role for IL-13 in the development of fibrosis in schistosomiasis, a chronic liver disease caused by the parasitic helminth Schistosoma mansoni. Since then, IL-13 has been shown to exhibit fibrotic activity in a variety of diseases and tissues, including models of chronic asthma, skin fibrosis, and bronchiolitis obliterans. A few recent studies have also suggested a role for IL-13 in bleomycin (BLM)-induced pulmonary fibrosis, a well-studied model of IPF. It has been suggested that IL-13 triggers fibrosis by inducing and activating TGF-β. Nevertheless, the mechanism of action of TGF-βin the development of pulmonary fibrosis remains controversial. Although it has been suggested that TGF-βcontributes to BLM-induced inflammation and fibrosis by stimulating fibroblast proliferation and collagen-producing myofibroblasts, recent studies also identified a critical role for TGF-βin the development of IL-17Aproducing CD4+ T cells, which regulate the pathogenesis of a variety of autoimmune and inflammatory diseases. Similarly, IL-1βcan stimulate IL-17A production, and IL-1βis a critical mediator of pulmonary fibrosis. To date, however, a link between IL-17Adriven inflammation and pulmonary fibrosis has not been established.
The aim of the current study was to characterize the mechanisms of pulmonary fibrosis and to determine whether IL-17A in particular plays an important regulatory role. To do this, three distinct model systems were used, including S. mansoni egg-induced pulmonary fibrosis, BLM-induced pulmonary fibrosis, and the recently described IL-1βdriven fibrosis. We found that S. mansoni egg-mediated fibrosis is IL-13 dependent, as il13−/−mice developed minimal fibrosis compared with WT mice. In marked contrast, BLM-induced pulmonary fibrosis was independent of IL-13 at early time points. Instead, studies with il17a−/−mice revealed a critical role for IL-17A. Using IL-10gfp reporter mice and newly generated IL-10 and IL-17A double cytokine-deficient animals, we determined that CD4+ cell-derived IL-10 is required to limit the production and frequency of IL-17A+CD4+ and IL-17A+γδ+ T cells, thus preventing the development of severe IL-17Adriven fibrosis. We also show that IL-17A is essential for the development of fibrosis in response to IL-1β, thus extending recent studies that described an early innate role for IL-1βin pulmonary fibrosis. Together, these studies demonstrate that fibrotic tissue remodeling is induced by distinct cytokine-dependent mechanisms, with the effector cytokines IL-13 and IL-17A playing central roles. Moreover, these findings suggest that TGF-βand proinflammatory mediators like IL-1βpromote fibrosis by up-regulating the production of IL-17A, thus identifying IL-17A blockade as a potential treatment for fibrotic diseases like IPF.
| 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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