79 : IL-6 regulation of Th1 responses drives fibrosis in unresolved inflammation

Abstract

Fibrosis in response to periodic infection is a complication of renal failure patients on peritoneal dialysis and suggests a failure to appropriately resolve inflammation. To mimic this situation a model of inflammation-induced peritoneal fibrosis was created by repeatedly challenging mice with a cell-free extract from Staphylococcus epidermidis (SES). Here, fibrosis was strictly interleukin (IL)-6 dependent, and showed no involvement of classical pro-fibrotic cytokines such as IL-4, IL-13 and SMAD3 signaling by TGF β . Instead, recurrent inflammation drove the IL-6-mediated expansion of interferon (IFN)- γ -secreting CD4 + Th1 cells, which promoted an emergence of STAT1 (Signal Transducer and Activator of Transcription-1) activity within the peritoneal membrane of repeatedly challenged mice. Increases in STAT1 activity were only seen in peritoneal membrane of wild type mice and was associated with the induction of STAT1 target genes (IRF-1, ISG-15). Fibrosis and alterations in STAT1 signaling was not observed in mice lacking IL-6, IFN γ , STAT1 or RAG1. Expansion of Th1 cells from naive T-cells required CD126 (IL6R) signaling and conditioned media from SES challenged resident peritoneal monocytic cells selectively promoted IFN γ , but not IL-4, IL-9, IL-13 or IL-17A, secreting CD4 + Tcells. SES did not however promote the innate production of IFN γ by CD19 + B-cells. While IL-6 deficient mice resisted fibrosis, transfer of SES polarized Th1 cells or inhibition of MMP activity through inclusion of RO32-355 (a broad spectrum MMP inhibitor) in drinking water reversed this outcome. Here, IFN γ /STAT1 signaling disrupted the turnover of extracellular matrix by metalloproteases (MMP-1, MMP-2, MMP-3, MMP-9). Thus, IL-6 causes compromised tissue repair by shifting acute inflammation into a more chronic pro-fibrotic state through induction of Th1 responses as a consequence of recurrent inflammation.