Select Effects of IL-13 in Driving Tissue Repair and Fibrosis

Abstract

Fibrosis is a common complication of solid organ transplantation, but whether it is due to maladaptive cell proliferation for tissue repair, direct fibroblast activation or a combination of both is not clear. Interleukin-13 (IL-13) has been associated with bronchiolitis obliterans syndrome (BOS) following lung transplantation in the clinic, and its inactivation in a mouse model of BOS was found to reduce fibro-obliteration (Keane et al.). Similarly, IL-13 has been linked with fibrosis of various organs, including the asthmatic lung, the skin in atopic dermatitis and the colon in ulcerative colitis, with clinical trials ongoing to test the therapeutic efficacy of targeting IL-13 in these disorders. In a recent issue of Immunity, Gieseck et al. use mouse models of progressive liver disease to dissect the precise effect of IL-13 on various hepatic cell subsets. Their results have implications for chronic transplant rejection. Fibroproliferative disease of the liver, which occurs following chronic viral or parasitic infections, or chronic rejection of hepatic allografts can include aberrant proliferation of hepatobiliary progenitor cells and bile duct epithelial cells (cholangiocytes) as well as a recruitment of inflammatory cells to the biliary ducts (ductular reaction [DR]), progressive development of ductal strictures, hepatic steatosis and fibrosis. The authors track these individual features in mouse models of schistosoma infection and chronic liver overexpression of IL-13 (following hydrodynamic injection of an IL-13 plasmid to transfected liver cells). Quite strikingly, abrogating expression of the IL-4Rα (a chain necessary for IL-4 and IL-13 receptor signaling) selectively in stellate cells (the liver-resident fibroblasts) using Il-4raflox/floxPdgfrbWT/cre mice, completely prevented development of fibrosis in both the chronic infection and sterile models. In contrast, steatosis and DR were unaffected. Conversely, eliminating IL-13 signaling only in hepatocytes and/or biliary cells using Il4raflox/floxAlbWT/cre mice reduced steatosis and DR without affecting fibrosis. The authors further ascribed these effects to IL-13–dependent rather than IL-4–dependent signals. The authors also found that biliary strictures observed in the IL-13 overexpression model were not due to fibrosis but likely caused by excessive ductal proliferation. The initial source of IL-13 in this disease is not certain, but both type 2 innate lymphoid cells (ILC2) and Th2 cells can make IL-13, and the authors demonstrate that IL-13 signaling in fibroblasts and hepatocytes promotes recruitment of eosinophils that in turn may further IL-13 production and pathological progression after initial injury. This paper clearly demonstrates the direct and distinct effect of IL-13 in different cell types and separates the processes of liver regeneration and liver fibrosis. The former, driven by hepatocytes and biliary cell response to IL-13, is desirable to repair liver injuries, but if triggered excessively, can lead to biliary stenosis and occlusions which themselves can lead to cholestatic steatosis. Gieseck and colleagues postulate that a reduction in bile output to the intestine results in malabsorption of fat from the diet, which may trigger a lipogenic program in hepatocytes to compensate for this reduction in dietary fat. In contrast, fibrosis is driven by the direct response from stellate cells to IL-13 and appears completely independent from DR and its accompanying inflammatory cells. Combined elimination of IL-13 signaling in stellate cells, hepatocytes and cholangiocytes may improve all features of liver fibroproliferative disease, although some level of tissue proliferation is likely important in response to acute injury. Another publication by the same group suggests that combined inhibition of IL-13 and interferon-γ (IFN-γ) can reduce not only the fibrotic but also the inflammatory features of shistosoma-induced liver disease (Ramalingam et al.). It is tempting to speculate that a similar approach may be beneficial to prevent chronic transplant rejection. In fact, extensive bile duct epithelial damage can occur during the ischemic period of organ harvest, which may trigger excessive tissue repair and fibrosis. Thus, IL-13 expression levels have the potential to be both a predictive biomarker of chronic rejection as well as a therapeutic target (perhaps in concert with IFN-γ) to limit liver remodeling and progressive dysfunction following transplantation. Dr. Alegre is a professor in the Department of Medicine at the University of Chicago.