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. Treating the individual sequelae of the metabolic syndrome associated with obesity and type 2 diabetes represents one way to alleviate the overall burden of disease. For example, nonalcoholic fatty liver disease (NAFLD), the hepatic manifestation of metabolic syndrome, is now the most common form of chronic liver disease, is growing in prevalence, and will soon be the most common cause of liver transplantation in the United States. This is highlighted by a recent estimate that NAFLD affects 64 million people in the United States, with annual direct medical costs projected at $103 billion. Although a great deal of research has focused on obesity, metabolic alterations in disease, adipose tissue dysregulation, and the pathophysiology of NAFLD, the molecular and immunological mechanisms that facilitate the progression of NAFLD to nonalcoholic steatohepatitis (NASH) and cirrhosis remain much less clear. Because severe cirrhosis is the ultimate reason patients require liver transplant and the presence of fibrosis has been identified as the best predictor of clinical outcome and mortality, a better understanding of the mechanisms that drive fibrogenesis in NAFLD could reveal novel treatment strategies and have a major impact on morbidity and mortality. However, progress in this area has been stymied by the absence of preclinical models that reliably reproduce inflammatory and fibrotic components seen in human disease. We investigated whether type 1 inflammatory response in obese mice directly contributes to the development of NAFLD. Using a variety of transgenic mice that develop highly polarized type 1 and type 2 immune responses, we examined whether the progression of high-fat diet (HFD)induced NASH and fibrosis is influenced by changes in type 2 immunity. Surprisingly, our studies reveal a disconnect in how obesity and the loss of type 2 effector function in adipose tissues affects the progression of inflammation, NASH, and fibrosis in the liver. In contrast to its protective role in metabolism, adipose tissue homeostasis, and obesity, we show that the type 2 cytokine IL-13 collaborates with transforming growth factor (TGF-) to drive liver fibrogenesis in HFD-induced obesity. 2. Disorders of the extrahepatic bile duct carry considerable morbidity and mortality. Indeed, 70% of pediatric liver transplantations are performed to treat biliary atresia, while primary sclerosing cholangitis (PSC) alone accounts for 5% of liver transplantations in the United States and biliary complications are the leading cause of graft failure following deceased donor liver transplantation3, 4. Treatment options remain limited owing to the lack of healthy donor tissue that can be used to reconstruct and replace diseased bile ducts. In vitro expansion of native cholangiocytes could address this limitation and provide cells suitable for tissue engineering applications such as biliary reconstruction. However, the culture of primary biliary epithelium remains problematic. Together with our collaborators at the University of Cambridge, we identified a new method, compatible with regenerative medicine applications, for the isolation and propagation of primary human cholangiocytes from the extrahepatic biliary tree. The resulting ECOs express key biliary markers, such as cytokeratin 7 (KRT7 or CK7), cytokeratin 19 (KRT19 or CK19), -glutamyl transferase (GGT) and cystic fibrosis transmembrane conductance regulator (CFTR), and maintain their functional properties in vitro, including alkaline phosphatase (ALP) and GGT activity and responses to secretin and somatostatin. The potential of ECOs in tissue engineering and clinical applications is further illustrated by their capacity to populate biodegradable scaffolds, organize into a functional biliary epithelium and rescue a mouse model of extrahepatic biliary injury (EHBI). 3. IL-4 and IL-13 are major T helper cell (Th) 2 cytokines implicated in the pathogenesis of several lung diseases, including pulmonary fibrosis. In this study, using a novel repetitive intradermal bleomycin model in which mice develop extensive lung fibrosis and a progressive decline in lung function compared to saline-treated control mice, we investigated profibrotic functions of Th2 cytokines. To determine the role of IL-13 signaling in the pathogenesis of bleomycin-induced pulmonary fibrosis, wild-type, IL-13, and IL-4R-deficient mice were treated with bleomycin, and lungs were assessed for changes in lung function and pulmonary fibrosis. Histological staining and lung function measurements demonstrated that collagen deposition and lung function decline were attenuated in mice deficient in either IL-13 or IL-4R-driven signaling compared to wild-type mice treated with bleomycin. Further, our results demonstrated that IL-13- and IL-4R-driven signaling are involved in excessive migration of macrophages and fibroblasts. Notably, our findings demonstrated that IL-13-driven migration involves increased pFAK signaling and F-actin polymerization. Importantly, in vivo findings demonstrated that IL-13 augments MMP2 and MMP9 activity that has also been shown to increase migration and invasiveness of fibroblasts in the lungs during bleomycin-induced pulmonary fibrosis. Together, our findings demonstrate a pathogenic role for Th2-cytokine signaling that includes excessive migration and protease activity involved in severe fibrotic lung disease.
| 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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