Abstract:AbstractAutotaxin (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… Show more
“…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.…”
Section: Increased Atx Staining In Spinal Cord Gfap + Cells During Eaesupporting
confidence: 86%
“…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.…”
Section: Increased Atx Staining In Spinal Cord Gfap + Cells During Eaesupporting
confidence: 68%
“…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.…”
Section: Introductionmentioning
confidence: 99%
“…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].…”
Autotaxin (ATX) is secreted by various type of cells in health and disease and catalyzes the extracellular production of lysophosphatidic acid (LPA). In turn, LPA is a bioactive lysophospholipid promoting a wide array of cellular functions through its multiple Gprotein coupled receptors, differentially expressed in almost all cell types. ATX expression has been shown necessary for embryonic development and has been suggested to participate in the pathogenesis of different chronic inflammatory diseases and cancer. Deregulated ATX and LPA levels have been reported in multiple sclerosis (MS) and its experimental model, experimental autoimmune encephalomyelitis (EAE). ATX genetic deletion from macrophages and microglia (CD11b + cells) attenuated the severity of EAE, thus proposing a pathogenic role for the ATX/LPA axis in MS/EAE. In this report, increased ATX staining was localized to glial fibrillary acidic protein positive (GFAP + ) cells, mostly astrocytes, in spinal cord sections from EAE mice at the peak of the disease. However, genetic deletion of ATX from GFAP + cells resulted in embryonic lethality, suggesting a major role for ΑΤΧ expression from GFAP + cells in embryonic development, that urges further dissection. Moreover, the re-expression of ATX from GFAP+ cells during the pathogenesis of EAE, reinforces the concept that ATX/LPA is a developmental program aberrantly reactivated upon chronic inflammation.
“…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.…”
Section: Increased Atx Staining In Spinal Cord Gfap + Cells During Eaesupporting
confidence: 86%
“…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.…”
Section: Increased Atx Staining In Spinal Cord Gfap + Cells During Eaesupporting
confidence: 68%
“…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.…”
Section: Introductionmentioning
confidence: 99%
“…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].…”
Autotaxin (ATX) is secreted by various type of cells in health and disease and catalyzes the extracellular production of lysophosphatidic acid (LPA). In turn, LPA is a bioactive lysophospholipid promoting a wide array of cellular functions through its multiple Gprotein coupled receptors, differentially expressed in almost all cell types. ATX expression has been shown necessary for embryonic development and has been suggested to participate in the pathogenesis of different chronic inflammatory diseases and cancer. Deregulated ATX and LPA levels have been reported in multiple sclerosis (MS) and its experimental model, experimental autoimmune encephalomyelitis (EAE). ATX genetic deletion from macrophages and microglia (CD11b + cells) attenuated the severity of EAE, thus proposing a pathogenic role for the ATX/LPA axis in MS/EAE. In this report, increased ATX staining was localized to glial fibrillary acidic protein positive (GFAP + ) cells, mostly astrocytes, in spinal cord sections from EAE mice at the peak of the disease. However, genetic deletion of ATX from GFAP + cells resulted in embryonic lethality, suggesting a major role for ΑΤΧ expression from GFAP + cells in embryonic development, that urges further dissection. Moreover, the re-expression of ATX from GFAP+ cells during the pathogenesis of EAE, reinforces the concept that ATX/LPA is a developmental program aberrantly reactivated upon chronic inflammation.
“…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).…”
Autotaxin (ATX; ENPP2) is a secreted lysophospholipase D catalysing the extracellular production of lysophosphatidic acid (LPA), a pleiotropic signalling phospholipid. Genetic and pharmacologic studies have previously established a pathologic role for ATX and LPA signalling in pulmonary injury, inflammation, and fibrosis. Here, increased ENPP2 mRNA levels were detected in immune cells from nasopharyngeal swab samples of COVID-19 patients, and increased ATX serum levels were found in severe COVID-19 patients. ATX serum levels correlated with the corresponding increased serum levels of IL-6 and endothelial damage biomarkers, suggesting an interplay of the ATX/LPA axis with hyperinflammation and the associated vascular dysfunction in COVID-19. Accordingly, dexamethasone (Dex) treatment of mechanically ventilated patients reduced ATX levels, as shown in two independent cohorts, indicating that the therapeutic benefits of Dex include the suppression of ATX. Moreover, large scale analysis of multiple single cell RNAseq datasets revealed the expression landscape of ENPP2 in COVID-19 and further suggested a role for ATX in the homeostasis of dendritic cells, that exhibit both numerical and functional deficits in COVID-19. Therefore, ATX has likely a multifunctional role in COVID-19 pathogenesis, worth of suggesting that its pharmacological targeting might represent an additional therapeutic option.
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