Liver Regeneration and Fibrosis are Concurrently but Independently Driven by Type-2 Immunity

FARE Award Winner

Authors

• RL Gieseck
• T Ramalingam
• K Hart
• K Vannella
• WY Lu
• S Ferreira-Gonzalez
• SJ Forbes
• L Vallier
• TA Wynn

Abstract

Fibroproliferative diseases are a major cause of morbidity and mortality in the developed world, with fibrosis affecting nearly every organ system in the body. Recent studies have suggested that type-2 cytokine responses are critically involved in both fibrosis and wound repair. However, the mechanisms that regulate beneficial repair versus pathological fibrosis are not well understood, particularly in the liver. In this study, we show that the Th2-effector cytokine interleukin-13 simultaneously, yet independently, directs hepatic fibrosis and the compensatory proliferation of the hepatocyte and biliary compartments. Using various cre-expressing mice to specifically disrupt interleukin-13 signaling in hepatocytes, biliary cells, and resident tissue fibroblasts during Schistosoma mansoni infection, we reveal a direct role for interleukin-13 signaling in each of these cell types and illustrate how each contributes to fibrosis and repair during chronic injury. Furthermore, using hydrodynamic delivery of interleukin-13 overexpression plasmids, we show that interleukin-13 can direct fibrosis, steatosis, hepatomegaly, and ductal proliferation in the absence of infection. Microarray analyses and studies with albumin and keratin-19 cre-expressing mice revealed that interleukin-13 overexpression disables bile acid synthesis, induces hepatic lipogenesis, and promotes the expansion and differentiation of hepatic progenitor cells. Moreover, studies with platelet derived growth factor receptor beta-cre expressing mice showed that interleukin-13 can instruct steatosis and ductal proliferation in the absence of significant fibrosis. We anticipate that these findings will prompt a new wave of clinical research investigating the therapeutic potential of interleukin-13 modulation in the pathogenesis of liver disease of various etiologies.

Scientific Focus Area: Microbiology and Infectious Diseases

This page was last updated on Friday, March 26, 2021