Inhibition of lysophosphatidic acid receptor 1-3 deteriorates experimental autoimmune encephalomyelitis by inducing oxidative stress

J Neuroinflammation. 2021 Oct 19;18(1):240. doi: 10.1186/s12974-021-02278-w.

Abstract

Background: Lysophosphatidic acid receptors (LPARs) are G-protein-coupled receptors involved in many physiological functions in the central nervous system. However, the role of the LPARs in multiple sclerosis (MS) has not been clearly defined yet.

Methods: Here, we investigated the roles of LPARs in myelin oligodendrocyte glycoprotein peptides-induced experimental autoimmune encephalomyelitis (EAE), an animal model of MS.

Results: Pre-inhibition with LPAR1-3 antagonist Ki16425 deteriorated motor disability of EAElow. Specifically, LPAR1-3 antagonist (intraperitoneal) deteriorated symptoms of EAElow associated with increased demyelination, chemokine expression, cellular infiltration, and immune cell activation (microglia and macrophage) in spinal cords of mice compared to the sham group. This LPAR1-3 antagonist also increased the infiltration of CD4+/IFN-γ+ (Th1) and CD4+/IL-17+ (Th17) cells into spinal cords of EAElow mice along with upregulated mRNA expression of IFN-γ and IL-17 and impaired blood-brain barrier (BBB) in the spinal cord. The underlying mechanism for negative effects of LPAR1-3 antagonist was associated with the overproduction of reactive oxygen species (ROS)-generating nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOX) 2 and NOX3. Interestingly, LPAR1/2 agonist 1-oleoyl-LPA (LPA 18:1) (intraperitoneal) ameliorated symptoms of EAEhigh and improved representative pathological features of spinal cords of EAEhigh mice.

Conclusions: Our findings strongly suggest that some agents that can stimulate LPARs might have potential therapeutic implications for autoimmune demyelinating diseases such as MS.

Keywords: Experimental autoimmune encephalomyelitis; Lysophosphatidic acid receptors; NADPH oxidase; Reactive oxygen species.

MeSH terms

  • Animals
  • Dose-Response Relationship, Drug
  • Encephalomyelitis, Autoimmune, Experimental / chemically induced
  • Encephalomyelitis, Autoimmune, Experimental / metabolism*
  • Female
  • Isoxazoles / pharmacology
  • Isoxazoles / toxicity*
  • Mice
  • Mice, Inbred C57BL
  • Myelin-Oligodendrocyte Glycoprotein / toxicity
  • Oxidative Stress / drug effects
  • Oxidative Stress / physiology*
  • Peptide Fragments / toxicity
  • Propionates / pharmacology
  • Propionates / toxicity*
  • Receptors, Lysophosphatidic Acid / antagonists & inhibitors
  • Receptors, Lysophosphatidic Acid / metabolism*

Substances

  • 3-(4-(4-((1-(2-chlorophenyl)ethoxy)carbonyl amino)-3-methyl-5-isoxazolyl) benzylsulfanyl) propanoic acid
  • Isoxazoles
  • LPAR2 protein, human
  • Lpar3 protein, mouse
  • Myelin-Oligodendrocyte Glycoprotein
  • Peptide Fragments
  • Propionates
  • Receptors, Lysophosphatidic Acid
  • lysophosphatidic acid receptor 1, mouse
  • myelin oligodendrocyte glycoprotein (35-55)