Pro-inflammatory cytokine TNFα antagonizes regulatory T cell (Treg) suppressive function with a measurable reduction of IL-10 protein secretion. Tregs are critical to suppress excessive immune activation, particularly within the intestine where high antigenic loads elicit chronic subclinical immune activation. Employing a TNFα-driven murine inflammatory bowel disease (IBD) model (TNFΔARE/+), which mirrors the Treg expansion and transmural ileitis seen in Crohn's disease, we demonstrate that the TNFα-mediated loss of Treg suppressive function coincides with induction of a specific miRNA, miR-106a in both humans and mice, via NFκB promoter binding to suppress post-transcriptional regulation of IL-10 release.... More
Pro-inflammatory cytokine TNFα antagonizes regulatory T cell (Treg) suppressive function with a measurable reduction of IL-10 protein secretion. Tregs are critical to suppress excessive immune activation, particularly within the intestine where high antigenic loads elicit chronic subclinical immune activation. Employing a TNFα-driven murine inflammatory bowel disease (IBD) model (TNFΔARE/+), which mirrors the Treg expansion and transmural ileitis seen in Crohn's disease, we demonstrate that the TNFα-mediated loss of Treg suppressive function coincides with induction of a specific miRNA, miR-106a in both humans and mice, via NFκB promoter binding to suppress post-transcriptional regulation of IL-10 release. Elevation of miR-106a and impaired Treg function in this model recapitulate clinical data from IBD patients. MiR-106a deficiency promotes Treg induction, suppressive function and IL-10 production in vitro. MiR-106a knockout attenuated chronic murine ileitis, whereas T cell restricted deficiency of miR-106a attenuated adoptive transfer colitis. In both models, attenuated inflammation coincided with suppression of both Th1 and Th17 cell subset expansion within the intestinal lamina propria. Collectively, our data demonstrate impaired Treg suppressive function in a murine IBD model consistent with human disease and support the potential for inhibition of miR-106a as a future therapeutic approach to treat chronic inflammatory conditions including IBD.
