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

Abstract

<jats:title>Abstract</jats:title><jats:p>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<jats:sup>+</jats:sup>CD11b<jats:sup>+</jats:sup> 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<jats:sup>+</jats:sup> cells attenuated the severity of EAE, thus proposing a pathogenic role for the ATX/LPA axis in neuroinflammatory disorders.</jats:p>

ATX expression from GFAP+cells is essential for embryonic development

“…Here, we show that a robust ATX signal co-localizes with GFAP + cells in spinal cord sections of relapsing as well as remitting EAE. As shown in Figure 1A, increased ATX expression was observed during EAE, peaking at the remission phase as previously reported [18]. Intense ATX staining was detected in astrocytes at the peak of the disease (GFAP + cells; Fig.…”

“…Increased ATX levels have been reported in the spinal cords of mice developing EAE; some of this ATX increase was attributed to activated CD11b + cell expression, mostly macrophages and microglia [18]. Here, we show that a robust ATX signal co-localizes with GFAP + cells in spinal cord sections of relapsing as well as remitting EAE.…”

“…In the CNS, ATX-dependent LPA signaling has been suggested to participate in initiation of neuropathic pain [4,11], while increased ATX expression has been reported in neuroblastomas and glioblastomas [12]. Deregulated ATX and LPA levels have been reported, with some controversy, in the sera and cerebrospinal fluid (CSF) of patients with multiple sclerosis (MS) [13][14][15][16][17], as well as in mice with experimental autoimmune encephalomyelitis (EAE) [17,18], suggesting a role for ATX/LPA in the pathogenesis of MS/EAE. Moreover, pharmacologic potent ATX inhibition has been reported to attenuate the development of EAE [19], further suggesting potential therapeutic benefits in targeting ATX in MS.…”

“…In the context of EAE, activated macrophages and microglia (F4/80 + CD11b + cells) were shown to express ATX, and ATX genetic deletion from CD11b+ cells attenuated the severity of EAE, suggesting an overall pathogenic role for ATX in MS/EAE pathogenesis [18]. However, increased ATX levels have been detected in activated astrocytes following neurotrauma, completely absent in physiological conditions [20].…”

Increased Autotaxin levels in severe COVID-19, correlating with IL-6 levels, endothelial dysfunction biomarkers, and impaired functions of dendritic cells

“…scRNAseq analysis of BALF cells from COVID-19 patients, where macrophages predominate, indicated that ENPP2 mRNA expression was detected in different macrophage subpopulations (Fig. 4C/UMAP, S3C/UMAP), where it could modulate their maturation in an autocrine mode via LPA (70)(71)(72). LPA has been also suggested to stimulate, in vitro, the conversion of monocytes to DCs (41,73,74).…”