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

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

doi:10.1371/journal.pone.0226050

Cited by 17 publications

(21 citation statements)

References 54 publications

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“…IPF macrophages have been previously shown to stain for ATX, and conditional genetic deletion of ATX from macrophages (LysM + cells) in mice, reduced BALF ATX levels and disease severity in modeled pulmonary fibrosis [ 20 ]. scRNAseq analysis of BALF cells from COVID-19 patients, where macrophages predominate, indicated that ENPP2 mRNA expression was detected in different macrophage subpopulations ( Figure 4 C/UMAP, S3C/UMAP), pending FACS validation, where it could modulate their maturation in an autocrine mode via LPA [ 79 , 80 , 81 ]. LPA has also been suggested to stimulate, in vitro, the conversion of monocytes to DCs [ 38 , 82 , 83 ].…”

Section: Discussionmentioning

confidence: 99%

Increased Autotaxin Levels in Severe COVID-19, Correlating with IL-6 Levels, Endothelial Dysfunction Biomarkers, and Impaired Functions of Dendritic Cells

Nikitopoulou

Fanidis

Ntatsoulis

et al. 2021

IJMS

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Autotaxin (ATX; ENPP2) is a secreted lysophospholipase D catalyzing the extracellular production of lysophosphatidic acid (LPA), a pleiotropic signaling phospholipid. Genetic and pharmacologic studies have previously established a pathologic role for ATX and LPA signaling 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 RNA sequencing datasets revealed the expression landscape of ENPP2 in COVID-19 and further suggested a role for ATX in the homeostasis of dendritic cells, which exhibit both numerical and functional deficits in COVID-19. Therefore, ATX has likely a multifunctional role in COVID-19 pathogenesis, suggesting that its pharmacological targeting might represent an additional therapeutic option, both during and after hospitalization.

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Section: Discussionmentioning

confidence: 99%

Increased Autotaxin Levels in Severe COVID-19, Correlating with IL-6 Levels, Endothelial Dysfunction Biomarkers, and Impaired Functions of Dendritic Cells

Nikitopoulou

Fanidis

Ntatsoulis

et al. 2021

IJMS

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“…scRNAseq analysis of BALF cells from COVID-19 patients indicated a predominance of macrophages ( 100 , 101 ), where ENPP2 mRNA expression was detected in monocyte-derived alveolar macrophages (Mo-AMs) ( 61 ), that have been shown to drive the development of BLM-induced pulmonary fibrosis in mice ( 105 ). In turn, accumulating evidence indicates that LPA co-stimulate macrophage maturation and/or activation ( 47 , 106 – 109 ), suggesting an autocrine role of ATX/LPA in macrophage pathologic responses. Moreover, LPA has been suggested to stimulate oxLDL uptake and foam cell formation ( 110 , 111 ), linking macrophages and ATX/LPA with hyperlipidaemia and cardiovascular diseases ( 112 ), major comorbidities of COVID-19.…”

Section: Lpa Signaling In Pulmonary and Immune Cellsmentioning

confidence: 99%

Commonalities Between ARDS, Pulmonary Fibrosis and COVID-19: The Potential of Autotaxin as a Therapeutic Target

et al. 2021

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Severe COVID-19 is characterized by acute respiratory distress syndrome (ARDS)-like hyperinflammation and endothelial dysfunction, that can lead to respiratory and multi organ failure and death. Interstitial lung diseases (ILD) and pulmonary fibrosis confer an increased risk for severe disease, while a subset of COVID-19-related ARDS surviving patients will develop a fibroproliferative response that can persist post hospitalization. Autotaxin (ATX) is a secreted lysophospholipase D, largely responsible for the extracellular production of lysophosphatidic acid (LPA), a pleiotropic signaling lysophospholipid with multiple effects in pulmonary and immune cells. In this review, we discuss the similarities of COVID-19, ARDS and ILDs, and suggest ATX as a possible pathologic link and a potential common therapeutic target.

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“…To investigate whether increases in serum ATX levels could exacerbate LPS-induced sepsis, transgenic mice overexpressing ATX in the liver under the control of the human α1-antitrypsin promoter (a1t1), resulting in ~200% increased serum ATX/LPA levels [ 8 , 22 , 23 , 24 ], were used. LPS was administered to homozygous transgenic mice (Tga1t1 Enpp2 ) and to their littermate controls, and the overall survival was studied.…”

Section: Resultsmentioning

confidence: 99%

“…However, transgenic ATX overexpression from the liver and the ensuing serum 200% ATX increases [ 22 ] did not exacerbate LPS-induced sepsis and lethality ( Figure 3 ). Of note, the increased systemic ATX levels in the same ATX transgenic mouse were previously shown not to significantly affect the development of modelled chronic inflammatory diseases, such as bleomycin-induced pulmonary fibrosis [ 8 ], transgenic TNF-driven inflammatory arthritis [ 23 ] or experimental autoimmune encephalomyelitis [ 24 ]. On the contrary, the transgenic ATX overexpression and the systemic serum ATX increases did exacerbate the development of CCl4-induced hepatitis [ 31 ], suggesting that systemic ATX can affect metabolic active tissues, such as the liver [ 31 , 32 ] or the muscle [ 33 ], and not just inflamed tissues.…”

Section: Discussionmentioning

confidence: 99%

Autotaxin Has a Negative Role in Systemic Inflammation

Nikitopoulou

Katsifa

Kanellopoulou

et al. 2022

IJMS

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The pathogenesis of sepsis involves complex interactions and a systemic inflammatory response leading eventually to multiorgan failure. Autotaxin (ATX, ENPP2) is a secreted glycoprotein largely responsible for the extracellular production of lysophosphatidic acid (LPA), which exerts multiple effects in almost all cell types through its at least six G-protein-coupled LPA receptors (LPARs). Here, we investigated a possible role of the ATX/LPA axis in sepsis in an animal model of endotoxemia as well as in septic patients. Mice with 50% reduced serum ATX levels showed improved survival upon lipopolysaccharide (LPS) stimulation compared to their littermate controls. Similarly, mice bearing the inducible inactivation of ATX and presenting with >70% decreased ATX levels were even more protected against LPS-induced endotoxemia; however, no significant effects were observed upon the chronic and systemic transgenic overexpression of ATX. Moreover, the genetic deletion of LPA receptors 1 and 2 did not significantly affect the severity of the modelled disease, suggesting that alternative receptors may mediate LPA effects upon sepsis. In translation, ATX levels were found to be elevated in the sera of critically ill patients with sepsis in comparison with their baseline levels upon ICU admission. Therefore, the results indicate a role for ATX in LPS-induced sepsis and suggest possible therapeutic benefits of pharmacologically targeting ATX in severe, systemic inflammatory disorders.

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

Cited by 17 publications

References 54 publications

Increased Autotaxin Levels in Severe COVID-19, Correlating with IL-6 Levels, Endothelial Dysfunction Biomarkers, and Impaired Functions of Dendritic Cells

Increased Autotaxin Levels in Severe COVID-19, Correlating with IL-6 Levels, Endothelial Dysfunction Biomarkers, and Impaired Functions of Dendritic Cells

Commonalities Between ARDS, Pulmonary Fibrosis and COVID-19: The Potential of Autotaxin as a Therapeutic Target

Autotaxin Has a Negative Role in Systemic Inflammation

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