Dysregulation of lysophosphatidic acids in multiple sclerosis and autoimmune encephalomyelitis

K Schmitz,N Ferreiros,K Scholich,C A Mayer,S Schiffmann,C Foerch,J Vogt,S Offermanns,J Chun,I Tegeder,S Tunaru,S Wicker,M J Parnham,R Brunkhorst,J Lötsch,A Häussler,N De Bruin,G Geisslinger

doi:10.1186/s40478-017-0446-4

Abstract

Bioactive lipids contribute to the pathophysiology of multiple sclerosis. Here, we show that lysophosphatidic acids (LPAs) are dysregulated in multiple sclerosis (MS) and are functionally relevant in this disease. LPAs and autotaxin, the major enzyme producing extracellular LPAs, were analyzed in serum and cerebrospinal fluid in a cross-sectional population of MS patients and were compared with respective data from mice in the experimental autoimmune encephalomyelitis (EAE) model, spontaneous EAE in TCR1640 mice, and EAE in Lpar2-/- mice. Serum LPAs were reduced in MS and EAE whereas spinal cord LPAs in TCR1640 mice increased during the ‘symptom-free’ intervals, i.e. on resolution of inflammation during recovery hence possibly pointing to positive effects of brain LPAs during remyelination as suggested in previous studies. Peripheral LPAs mildly re-raised during relapses but further dropped in refractory relapses. The peripheral loss led to a redistribution of immune cells from the spleen to the spinal cord, suggesting defects of lymphocyte homing. In support, LPAR2 positive T-cells were reduced in EAE and the disease was intensified in Lpar2 deficient mice. Further, treatment with an LPAR2 agonist reduced clinical signs of relapsing-remitting EAE suggesting that the LPAR2 agonist partially compensated the endogenous loss of LPAs and implicating LPA signaling as a novel treatment approach.Graphical abstractGraphical summary of lysophosphatidic signaling in multiple sclerosis

Highlights

Lysophosphatidic acids (LPAs) are lipid-signaling molecules of different chain lengths and phosphorylation
As healthy subjects were younger than multiple sclerosis (MS) patients (Demographic Table 1) the analysis was repeated for subsets of gender and age matched patients and controls > 30 years
Linear regression analyses did not show a significant association of the sum of all LPAs with age or body mass index (BMI) in healthy controls or age in MS patients (R2 = 2.435, P = 0.115)

Summary

Introduction

Lysophosphatidic acids (LPAs) are lipid-signaling molecules of different chain lengths and phosphorylation. Signal transduction through LPARs regulates cell mobility and migration [25, 71], neuro - and angiogenesis [62], and platelet aggregation [43] Their functions in the context of multiple sclerosis (MS) are presently unknown. There are two major pathways for extracellular LPA production [37]: (i) by direct hydrolysis of a fatty acid moiety from membrane-derived phosphatidic acid [18] and (ii) by removal of the choline moiety from the abundant lysophosphatidylcholine (LPC) [56, 60] The latter process is mediated by autotaxin (ATX), a secreted lysophospholipase D (lyso-PLD), which is a multidomain

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Discussion

Conclusion