Activation of macrophages by lysophosphatidic acid through the lysophosphatidic acid receptor 1 as a novel mechanism in multiple sclerosis pathogenesis

Multiple sclerosis (MS) is a neuro-inflammatory disease for which the pathogenesis remains largely unclear. Lysophosphatidic acid (LPA) is an endogenous phospholipid that is involved in multiple immune cell functions and is dysregulated in MS. Its receptor LPA 1 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 viable Malaga variant of LPA 1 -null mutation as well as pharmaceutical inhibition of LPA 1 in mice with experimental autoimmune encephalomyelitis (EAE), a model of MS. LPA 1 expression was also analyzed in both wild-type EAE mice and MS patient immune cells. The effect of LPA and LPA 1 on macrophage activation was studied in human monocyte-derived macrophages. We show that lack of LPA 1 activity induces a milder clinical course in EAE, and that Lpar1 expression in peripheral blood mononuclear cells (PBMCs) correlates with onset of relapses and severity in wild-type EAE mice. We see the same over-expression in PBMCs from MS patients during relapse compared to progressive forms of the disease, and in monocyte-derived macrophages after exposure to pro-inflammatory stimuli. In addition, LPA induced a pro-inflammatory-like response in macrophages through LPA 1 , providing a plausible way in which LPA and LPA 1 dysregulation can lead to the inflammation seen in MS. These data show a new mechanism of LPA signaling in the pathogenesis of MS, prompting further research into its use as a therapeutic target biomarker.