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A murine model of meningeal inflammation and subpial demyelination identifies an anti-MOG independent mechanism of cortical injury that is inhibited by Siponimod therapy

Ward, Lesley A and Lee, Dennis SW and Sharma, Anshu and Wang, Angela and Naouar, Ikbel and Ma, Xianjie I and Pikor, Natalia and Nuesslein-Hildesheim, Barbara and Ramaglia, Valeria and Gommerman, Jennifer L (2020) A murine model of meningeal inflammation and subpial demyelination identifies an anti-MOG independent mechanism of cortical injury that is inhibited by Siponimod therapy. JCI insight.

Abstract

Subpial demyelination is a specific hallmark of multiple sclerosis (MS) and a correlate of
disease progression and cognitive decline. Although the mechanism(s) that mediate
pathogenesis in this compartment remain unclear, it has been speculated that inflammation in
the overlying meninges may be associated with sub-pial injury. We have previously shown that
proteolipid-primed Th17 cells adoptively transferred into SJL/J recipient mice induce
Experimental Autoimmune Encephalomyelitis (A/T SJL/J EAE) accompanied by extensive
stromal cell remodelling and accumulation of lymphocytes in the brain meninges. Here we
show that meningeal inflammation in this model overlays areas of subpial cortical
demyelination associated with microglial/macrophage activation, disruption of the glial
limitans and evidence of an oxidative stress response. These pathological features were
observed even in the absence of measurable anti-MOG IgM or IgG antibodies. We took
advantage of this model to test potential mechanisms of action of BAF312 (siponimod), a
selective sphingosine 1-phosphate (S1P) receptor1,5 modulator. BAF312 treatment
significantly ameliorated clinical manifestations of EAE concomitant with diminished
meningeal inflammation and subpial pathology and as well as a selective reduction in Th17
cell accumulation in the central nervous system (CNS). We conclude that Th17 cells rather
than anti-MOG antibodies are critically required for meningeal inflammation and cortical
pathology in A/T SJL/J EAE. Moreover BAF312, a promising MS therapeutic, ameliorates the
clinical and pathological features of this model perhaps through its affect on CNS-resident
Th17 cells.

Item Type: Article
Date Deposited: 19 May 2020 00:45
Last Modified: 19 May 2020 00:45
URI: https://oak.novartis.com/id/eprint/40457

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