Genetic deletion of Autotaxin from CD11b+ cells decreases the severity of experimental autoimmune encephalomyelitis.

Ioanna Ninou,Ioanna Sevastou,George Panayotou,Spyros Thivaios,Christiana Magkrioti,Junken Aoki,George Kollias,George Stamatakis,Eleanna Kaffe,Vassilis Aidinis,Ari Waisman

doi:10.1371/journal.pone.0226050

Abstract

Autotaxin (ATX) is a secreted lysophospholipase D catalyzing the extracellular production of lysophosphatidic acid (LPA), a growth factor-like signaling lysophospholipid. ATX and LPA signaling have been incriminated in the pathogenesis of different chronic inflammatory diseases and various types of cancer. In this report, deregulated ATX and LPA levels were detected in the spinal cord and plasma of mice during the development of experimental autoimmune encephalomyelitis (EAE). Among the different sources of ATX expression in the inflamed spinal cord, F4/80+ CD11b+ cells, mostly activated macrophages and microglia, were found to express ATX, further suggesting an autocrine role for ATX/LPA in their activation, an EAE hallmark. Accordingly, ATX genetic deletion from CD11b+ cells attenuated the severity of EAE, thus proposing a pathogenic role for the ATX/LPA axis in neuroinflammatory disorders.

Highlights

Multiple sclerosis (MS) is the most common debilitating disorder of the central nervous system (CNS), imposing a substantial personal, and socioeconomic burden [1]
To explore a possible involvement of the ATX/lysophosphatidic acid (LPA) axis in the pathophysiology of EAE, C57Bl6/J male mice were immunized with myelin oligodendrocyte glycoprotein (MOG), following a widely used EAE protocol (Fig 1A)[2]
Increased ATX levels and deregulated lipid homeostasis in the inflamed spinal cord In order to examine if LPA homeostasis and signaling are perturbed upon EAE locally in spinal cords, where EAE predominately manifests in this model [2], we examined ATX and LPA levels, as well as the mRNA levels of several key players in LPA metabolism and signaling

Summary

Introduction

Multiple sclerosis (MS) is the most common debilitating disorder of the central nervous system (CNS), imposing a substantial personal, and socioeconomic burden [1]. Despite the inherent limitations of modeling a human disease in experimental animals, valuable insights into MS pathophysiology were provided by the model of experimental autoimmune encephalomyelitis (EAE), that can be induced by immunizing animals against myelin antigens [2]. In this context, current research suggests that inflammation is a prominent feature of MS pathogenesis, initiated by autoreactive lymphocytes in the periphery and substantiated by leakage of the blood-brain barrier (BBB)[3]. Neuroinflammation leads to microglial and astrocyte activation, astrogliosis and eventually to demyelination, axonal or neuronal loss

Methods

Results

Discussion

Conclusion