S-13 : Interleukin-6 drives tissue fibrosis in response to repeat acute inflammation

Abstract

Aims: Appropriate control of acute inflammation in response to bacterial infection ensures competent host defense, whilst limiting adverse inflammation-induced injury. Recurrent bouts of infection however drive tissue damage or fibrosis. Studies examined the mechanisms that underpin these differences in inflammatory outcome. Methods: Studies examined the cellular events that dictate transition of an acute resolving inflammatory response into a more damaging inflammatory setting. Peritonitis provides an excellent opportunity to evaluate this process, since recurrent infections in renal failure patients on peritoneal dialysis is a major reason for treatment failure. Here, the frequency or severity of peritonitis correlates with increased tissue fibrosis, vascular damage and retention of activated leukocytes in the peritoneal cavity. We therefore developed a novel murine model of peritoneal inflammation, which promotes peritoneal fibrosis following repeated challenge with a microbial-derived stimulus (SES). This approach allowed us to track temporal changes in the inflammation that affect peritoneal cytokine production, leukocyte recruitment and activation, and the response of the resident stromal tissue. Results: Fibrosis was strictly interleukin (IL)-6 dependent. Repeat inflammation induced IL-6-mediated T-helper 1 (Th1) cell effector commitment and the emergence of STAT1 (Signal Transducer and Activator of Transcription-1) activity within the peritoneal membrane. Fibrosis was not observed in mice lacking interferon (IFN)-g, STAT1 or RAG-1. Here, IFN-g and STAT1 signaling disrupted the turnover of extracellular matrix by metalloproteases. Whereas IL-6 deficient mice resisted fibrosis, transfer of polarised Th1 cells or inhibition of MMP activity reversed this outcome. Conclusions: Interleukin-6 causes compromised tissue repair by shifting acute inflammation into a more chronic pro-fibrotic state through induction of Th1 cell responses as a consequence of recurrent inflammation. Here, recurrent innate inflammatory activation inadvertently promote adaptive immune responses that alter the pattern of cytokine signaling in stromal tissue, which ultimately gives rise to fibrosis and chronicity.