Lincoln, M. R. | Search bioRxiv

bioRxiv2018

PTGER2-β-Catenin Axis Links High Salt Environments to Autoimmunity by Balancing IFNγ and IL-10 in FoxP3+ Regulatory T cells

Foxp3+ regulatory T cells (Tregs) are the central component of peripheral immune tolerance. While dysregulation of the Treg cytokine signature has been observed in autoimmune diseases such as multiple sclerosis (MS) and type 1 diabetes, the regulatory mechanisms balancing pro- and anti-inflammatory cytokine production are not known. Here, we identify imbalance between IFN{gamma} and IL-10 as a shared Treg signature, present in patients with MS and under high salt conditions. By performing RNA-seq analysis on human Treg subpopulations, we identify {beta}-catenin as a key regulator that controls the expression of IFN{gamma} and IL-10. The activated {beta}-catenin signature is enriched specifically in IFN{gamma}+Tregs in humans, and this was confirmed in vivo with Treg-specific {beta}-catenin-stabilized mice exhibiting lethal autoimmunity with a dysfunctional, IFN{gamma}-producing, Treg phenotype. Moreover, we identify PTGER2 as a major factor balancing IFN{gamma} and IL-10 production in the context of a high salt environment, with skewed activation of the {beta}-catenin/SGK1/Foxo axis in IFN{gamma}+Tregs. These findings identify a novel molecular mechanism underlying inflammatory Tregs in human autoimmune disease and reveal a new role for a PTGER2-{beta}-catenin loop in Tregs linking environmental high salt conditions to autoimmunity.

immunology↗

bioRxiv2017

Enhanced Astrocyte Responses are Driven by a Genetic Risk Allele Associated with Multiple Sclerosis

Epigenetic annotation studies of genetic risk variants for multiple sclerosis (MS) implicate dysfunctional lymphocytes in MS susceptibility; however, the role of central nervous system (CNS) cells remains unclear. We investigated the effect of the risk variant, rs7665090G, located near NFKB1, on astrocytes. We demonstrated that chromatin is accessible at the risk locus, a prerequisite for its impact on astroglial function. The risk variant was associated with increased NF-{kappa}B signaling and target gene expression driving lymphocyte recruitment in cultured human astrocytes and astrocytes within MS lesions, and with increased lesional lymphocytic infiltrates. In MS patients, the risk genotype was associated with increased lesion volumes on MRI. Thus, we established that the rs7665090G variant perturbs astrocyte function resulting in increased CNS access for peripheral immune cells. MS may thus result from variant-driven dysregulation of the peripheral immune system and the CNS, where perturbed CNS cell function aids in establishing local autoimmune inflammation.\n\nOne Sentence SummaryThe NF-{kappa}B relevant multiple sclerosis risk variant, rs7665090G, drives astrocyte responses that promote lesion formation.

neuroscience↗