Dysregulation of intestinal IL17 signaling & the microbiome exacerbate autoimmune neuroinflammation.

Abstract

Abstract Multiple sclerosis (MS) is a chronic autoimmune disorder of the central nervous system (CNS). Studies in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, strongly indicate that both Th17 cells and the commensal microbiome modulate disease pathogenesis. The commensal, segmented filamentous bacteria (SFB), regulates Th17 responses. Given the relationship between commensals and Th17 cells and the role of each of these factors in EAE, we investigated the significance of enteric IL-17R signaling in EAE using intestinal specific IL-17 receptor knockouts (Il17ra/rcfl/flx villin cre+ mice). We hypothesized that disruption of the reciprocal regulatory relationship between enteric IL-17 signaling and the gut microbiota leads to dysbiosis, expansion of Th17 cells, and increased predisposition to autoimmune neuroinflammation. Our data suggested that Il17ra/rcfl/fl x villin cre+ mice, which have higher SFB levels, exhibit earlier EAE onset and increased EAE severity and incidence as compared to littermate cre− controls. Treatment with vancomycin ameliorated disease, further supporting our hypothesis. In addition, preliminary data indicated that cre+ mice have increased CCR2 and CCR6 gut expression at baseline. At day 9-post immunization in the same mice, there was increased expression of CCR2 and Nox2 in the spinal cord and Csf2 in the gut. Together, this suggested that there could be increased migration into the CNS of cre+ mice, contributing to exacerbated disease. These studies will make a significant conceptual advance by elucidating how dysregulation of enteric IL-17R signaling and the commensal microbiota contribute to the pathogenesis of autoimmune conditions such as Multiple Sclerosis.