Activation of Macrophages by Lysophosphatidic Acid through the Lysophosphatidic Acid Receptor 1 as a Novel Mechanism in
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Activation of Macrophages by Lysophosphatidic Acid through the Lysophosphatidic Acid Receptor 1 as a Novel Mechanism in Multiple Sclerosis Pathogenesis Jennifer Fransson 1,2 & Ana Isabel Gómez-Conde 3 & Jesús Romero-Imbroda 3 & Oscar Fernández 3 & Laura Leyva 3 & Fernando Rodríguez de Fonseca 3 & Jerold Chun 4 & Celine Louapre 1,2,5 & Anne Baron Van-Evercooren 1,2 & Violetta Zujovic 1,2 & Guillermo Estivill-Torrús 3 & Beatriz García-Díaz 1,2,3 Received: 11 June 2020 / Accepted: 14 September 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Multiple sclerosis (MS) is a neuroinflammatory disease whose pathogenesis remains unclear. Lysophosphatidic acid (LPA) is an endogenous phospholipid involved in multiple immune cell functions and dysregulated in MS. Its receptor LPA1 is expressed in macrophages and regulates their activation, which is of interest due to the role of macrophage activation in MS in both destruction and repair. In this study, we studied the genetic deletion and pharmaceutical inhibition of LPA1 in the mouse MS model, experimental autoimmune encephalomyelitis (EAE). LPA1 expression was analyzed in EAE mice and MS patient immune cells. The effect of LPA and LPA1 on macrophage activation was studied in human monocyte-derived macrophages. We show that lack of LPA1 activity induces milder clinical EAE course and that Lpar1 expression in peripheral blood mononuclear cells (PBMC) correlates with onset of relapses and severity in EAE. We see the same over-expression in PBMC from MS patients during relapse compared with progressive forms of the disease and in stimulated monocyte-derived macrophages. LPA induced a proinflammatory-like response in macrophages through LPA1, providing a plausible way in which LPA and LPA1 dysregulation can lead to the inflammation in MS. These data show a new mechanism of LPA signaling in the MS pathogenesis, prompting further research into its use as a therapeutic target biomarker. Keywords Lysophosphatidic acid . LPA 1 receptor . Macrophages . Multiple sclerosis . Experimental autoimmune encephalomyelitis . Inflammation
Abbreviations CNS central nervous system EAE experimental autoimmune encephalomyelitis HD healthy donors IMNC infiltrating mononuclear cell
KO LPA MS OPC PBMC
knockout lysophosphatidic acid multiple sclerosis oligodendrocyte precursor cell peripheral blood mononuclear cell
Guillermo Estivill-Torrús and Beatriz García-Díaz contributed equally to this work. * Guillermo Estivill-Torrús [email protected] * Beatriz García-Díaz [email protected]; [email protected] 1
Institut du Cerveau et de la Moelle Epinière-Groupe Hospitalier Pitié-Salpêtrière, INSERM, U1127, CNRS, UMR 7225, F-75013 Paris, France
2
Sorbonne Universités, Université Pierre et Marie Curie Paris 06, UM-75, F-75005 Paris, France
3
Unidad de Gestión Clínica de Neurociencias, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Regional Universitario de Málaga, Málaga, Spain
4
Sanford Burnham Prebys Medical Discovery Institut
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