IL-10 and the JAK-STAT Pathway in the Regulation of Metabolism and Mucosal Homeostasis

Abstract

The JAK-STAT pathway integrates signals from multiple cytokines to elicit a specific output, and aberrations in this pathway contribute to the pathogenesis of multiple diseases such as inflammatory bowel disease (IBD). Interleukin 10 (IL-10), for example, utilizes STAT3 to suppress inflammation, and mutations in IL-10 or its receptor have been associated with IBD. However, it is currently unclear how the JAK-STAT pathway achieves specificity and how it contributes to IBD. Here, we investigate the roles of STAT1 in IBD and STAT3 in IL-10R signaling. We first investigated how CD4+ T cells use STAT1 to drive intestinal inflammation. In an adoptive transfer model, Stat1-/- T cells are unable to expand and induce colitis. This defect is only partially explained by the loss of Type I and II interferon signaling. Mechanistically, Stat1-/- T cells display reduced expression of Nlrc5 and multiple MHC class I molecules, which are inhibitors of NK cell killing. Consequently, NK cell depletion significantly rescues the survival of Stat1-/- T cells and restores colitis induction. Interestingly, only Stat1-/- T cells that underwent spontaneous proliferation are eliminated, suggesting that NK cells specifically target microbially activated T cells. Stat1-/- mice have normal CD4+ T cell numbers as innate STAT1 signaling is required for their elimination. Together, our data points to a critical role for STAT1 in shielding T cells from NK cell mediated cytotoxicity. Next, we investigated how IL-10 utilizes STAT3 to achieve specificity, hypothesizing that IL-10-STAT3 might exhibit non-canonical functions outside of the nucleus. We show that, in addition to the nucleus, IL-10 also induces activated pSTAT3 in macrophage mitochondria. Upon acute IL-10 stimulation, STAT3 interacted with multiple mitochondrial proteins. This correlated with metabolic changes that indicate enhanced functions of these proteins. STAT3’s DNA binding activity is not required for IL-10 to inhibit pro-inflammatory gene expression, suggesting that non-transcriptional functions of STAT3 are sufficient for IL-10 mediated suppression. However, IL-10 requires STAT3 mediated transcription to enhance anti-inflammatory M2 macrophage polarization, suggesting that IL-10-dependent non-canonical STAT3 acts specifically to regulate the metabolic state during inflammation. Together, our data reveals a novel mechanism of IL-10R-STAT3 signaling that might explain its immunosuppressive effects.