Histone Demethylase JARID1C/KDM5C Regulates Th17 T Cells in Diabetic Wounds by Increasing IL-6 Expression in Plasmacytoid Dendritic Cells

Abstract

Plasmacytoid dendritic cells (pDCs) are first responders to tissue damage and interact with wound CD4 T cells to orchestrate tissue repair. In diabetes, the role of pDCs and their subsequent influence on wound CD4+ T cells and inflammation during tissue repair is unknown. Using human diabetic wound single cell sequencing, we identified that human wound CD4+ T-cells are primarily of the inflammatory TH17 phenotype. Thus, we hypothesized that pDCs in the wounds may regulate this T-cell phenotype, contributing to chronic inflammation. We utilized human diabetic wound single cell sequencing and analyzed murine wounds from diabetic and nondiabetic mice. These tissue were subjected to pDC isolation by magnetic sorting, flow cytometry, chromatin immunoprecipitation, quantitative polymerase chain reaction, histone arrays, and enzyme-linked immunosorbent assays. We found that diabetic pDC produced significantly more IL-6 compared to controls. This is important as IL-6 has been shown to skew CD4+ T cells toward a TH-17 phenotype in tissues. We identified that histone demethylase JARID1C was significantly decreased in diabetic pDCs compared to controls. JARID1C is an epigenetic enzyme responsible for demethylating lysine 4 on histone 3, resulting in gene transcription inhibition. We demonstrate that type 1 interferons regulate JARID1C expression via TYK2/JAK1,3 mechanism. Finally, we show that in vitro administration of recombinant JARID1C decreases IL-6 production and TH17 T-cell expression. Taken together, these data suggest that, in diabetes, pDCs are epigenetically altered to increase IL-6 expression and direct the adaptive immune response toward pathologic TH17 CD4+ T-cell-mediated chronic inflammation and poor wound healing.