LPA1 signaling drives Schwann cell dedifferentiation in experimental autoimmune neuritis

Fabian Szepanowski,Maximilian Winkelhausen,Mark Stettner,Christoph Kleinschnitz,Rebecca D Steubing,Anne K Mausberg

doi:10.1186/s12974-021-02350-5

Abstract

BackgroundLysophosphatidic acid (LPA) is a pleiotropic lipid messenger that addresses at least six specific G-protein coupled receptors. Accumulating evidence indicates a significant involvement of LPA in immune cell regulation as well as Schwann cell physiology, with potential relevance for the pathophysiology of peripheral neuroinflammation. However, the role of LPA signaling in inflammatory neuropathies has remained completely undefined. Given the broad expression of LPA receptors on both Schwann cells and cells of the innate and adaptive immune system, we hypothesized that inhibition of LPA signaling may ameliorate the course of disease in experimental autoimmune neuritis (EAN).MethodsWe induced active EAN by inoculation of myelin protein 2 peptide (P255–78) in female Lewis rats. Animals received the orally available LPA receptor antagonist AM095, specifically targeting the LPA1 receptor subtype. AM095 was administered daily via oral gavage in a therapeutic regimen from 10 until 28 days post-immunization (dpi). Analyses were based on clinical testing, hemogram profiles, immunohistochemistry and morphometric assessment of myelination.ResultsLewis rats treated with AM095 displayed a significant improvement in clinical scores, most notably during the remission phase. Cellular infiltration of sciatic nerve was only discretely affected by AM095. Hemogram profiles indicated no impact on circulating leukocytes. However, sciatic nerve immunohistochemistry revealed a reduction in the number of Schwann cells expressing the dedifferentiation marker Sox2 paralleled by a corresponding increase in differentiating Sox10-positive Schwann cells. In line with this, morphometric analysis of sciatic nerve semi-thin sections identified a significant increase in large-caliber myelinated axons at 28 dpi. Myelin thickness was unaffected by AM095.ConclusionThus, LPA1 signaling may present a novel therapeutic target for the treatment of inflammatory neuropathies, potentially affecting regenerative responses in the peripheral nerve by modulating Schwann cell differentiation.

Highlights

Immune-mediated neuropathies represent a heterogeneous group of rare peripheral nerve disorders comprising both acute and chronic forms
While the detrimental effects of innate and adaptive immune responses have been welldefined in autoimmune neuropathies [5], demyelination does not appear to be an exclusive result of self-directed immunity, but rather a result of Schwann cell dedifferentiation and the adoption of a non-myelinating phenotype in the inflammatory milieu via the secretion of cytokines and various other cues from T-lymphocytes and their effector cells [6]
AM095 accelerates recovery in active experimental autoimmune neuritis (EAN) by clinical and morphometric measures Following the induction of active EAN, rats were monitored daily and clinical scores were determined until 28 days postimmunization

Summary

Introduction

Immune-mediated neuropathies represent a heterogeneous group of rare peripheral nerve disorders comprising both acute and chronic forms. Given the substantial body of evidence indicating autoimmune-driven damage to neurons and glial cells as major pathological hallmark of inflammatory neuropathies, cellular and humoral immune responses against the peripheral nervous system (PNS) have mostly been considered in isolation, largely ignoring the acute and potentially long-lasting impact on physiological homeostasis in the peripheral nerve. While the detrimental effects of innate and adaptive immune responses have been welldefined in autoimmune neuropathies [5], demyelination does not appear to be an exclusive result of self-directed immunity, but rather a result of Schwann cell dedifferentiation and the adoption of a non-myelinating phenotype in the inflammatory milieu via the secretion of cytokines and various other cues from T-lymphocytes and their effector cells [6]. Given the broad expression of LPA receptors on both Schwann cells and cells of the innate and adaptive immune system, we hypothesized that inhibition of LPA signaling may ameliorate the course of disease in experimental autoimmune neuritis (EAN)

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