Enhanced astrocyte responses are driven by a genetic risk allele associated with multiple sclerosis

Gerald Ponath,Cedric S Raine,Calvin Park,Thanh D Nguyen,Mayyan Mubarak,Maya Levine-Ritterman,Laura Airas,Somiah Dahlawi,Shun Zhang,David Pitt,Tomokazu Sumida,David A Hafler,Cigdem Isitan,Matthew R Lincoln

doi:10.1038/s41467-018-07785-8

Abstract

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-κB signaling and target gene expression, driving lymphocyte recruitment, in cultured human astrocytes and astrocytes within MS lesions, and with increased lesional lymphocytic infiltrates and lesion sizes. Thus, our study establishes a link between genetic risk for MS (rs7665090G) and dysfunctional astrocyte responses associated with increased CNS access for peripheral immune cells. MS may therefore result from variant-driven dysregulation of the peripheral immune system and of the CNS, where perturbed CNS cell function aids in establishing local autoimmune inflammation.

Highlights

Epigenetic annotation studies of genetic risk variants for multiple sclerosis (MS) implicate dysfunctional lymphocytes in MS susceptibility; the role of central nervous system (CNS) cells remains unclear
In the present study, we examined the impact of a risk variant for MS susceptibility, rs7665090G, on astrocyte function both in vitro and in active MS lesions, as well as on lesion pathology
We demonstrated that the risk variant is associated with enhanced astroglial NF-κB signaling and upregulation of a subset of NF-κB target genes that drive lymphocyte recruitment and neurotoxicity, as implied by increased expression of C38

Summary

Introduction

Epigenetic annotation studies of genetic risk variants for multiple sclerosis (MS) implicate dysfunctional lymphocytes in MS susceptibility; the role of central nervous system (CNS) cells remains unclear. Our study establishes a link between genetic risk for MS (rs7665090G) and dysfunctional astrocyte responses associated with increased CNS access for peripheral immune cells. MS may result from variant-driven dysregulation of the peripheral immune system and of the CNS, where perturbed CNS cell function aids in establishing local autoimmune inflammation We addressed this question by investigating how a common MS risk variant, rs7665090G, which is relevant to NF-κB signaling, changes astrocyte function. This risk variant has an approximate frequency of 55% in the general population, and increases the odds ratio for MS susceptibility by 1.09 per G allele carried[4], and has recently been shown to substantially increase NF-κB p50 expression and NF-κB activation in lymphocytes[5]. Our results provide compelling evidence that genetic MS risk is linked to the dysregulation of astrocyte function

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