Dysregulation of lysophosphatidic acids in multiple sclerosis and autoimmune encephalomyelitis

  • 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.

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Author:Katja Schmitz, Robert BrunkhorstGND, Natasja de BruinORCiD, Christoph Mayer, Annett Häussler, Nerea Ferreirós BouzasORCiDGND, Susanne SchiffmannORCiDGND, Michael J. ParnhamORCiDGND, Sorin TunaruORCiDGND, Jerold ChunORCiDGND, Stefan OffermannsORCiDGND, Christian FörchORCiDGND, Klaus ScholichORCiD, Johannes VogtORCiD, Sabine WickerORCiDGND, Jörn LötschORCiDGND, Gerd GeisslingerORCiDGND, Irmgard TegederORCiDGND
URN:urn:nbn:de:hebis:30:3-456057
DOI:https://doi.org/10.1186/s40478-017-0446-4
ISSN:2051-5960
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/28578681
Parent Title (English):Acta Neuropathologica Communications
Publisher:Biomed Central
Place of publication:London
Document Type:Article
Language:English
Year of Completion:2017
Date of first Publication:2017/06/02
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2018/02/01
Tag:Autoimmune encephalomyelitis; Lpar2; Lysophosphatidic acids; Neuroinflammation; Spinal cord; T-cell homing; multiple sclerosis
Volume:5
Issue:1, Art. 42
Page Number:18
First Page:1
Last Page:18
Note:
© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
HeBIS-PPN:426710118
Institutes:Biochemie, Chemie und Pharmazie / Pharmazie
Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 4.0