Dysregulation of lysophosphatidic acids in multiple sclerosis and autoimmune encephalomyelitis

• Main Authors: K. Schmitz, R. Brunkhorst, N. de Bruin, C. A. Mayer, A. Häussler, N. Ferreiros, S. Schiffmann, M. J. Parnham, S. Tunaru, J. Chun, S. Offermanns, C. Foerch, K. Scholich, J. Vogt, S. Wicker, J. Lötsch, G. Geisslinger, I. Tegeder
• Format: Article
• Language: English
• Published: BMC 2017-06-01
• Series: Acta Neuropathologica Communications
• Subjects: Lysophosphatidic acids; Multiple sclerosis; Autoimmune encephalomyelitis; Lpar2; Neuroinflammation; Spinal cord
• Online Access: http://link.springer.com/article/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 abstract Graphical summary of lysophosphatidic signaling in multiple sclerosis