Phospholipase A1 Member A Activates Fibroblast-like Synoviocytes through the Autotaxin-Lysophosphatidic Acid Receptor Axis

Int J Mol Sci. 2021 Nov 24;22(23):12685. doi: 10.3390/ijms222312685.

Abstract

Lysophosphatidylserine (lysoPS) is known to regulate immune cell functions. Phospholipase A1 member A (PLA1A) can generate this bioactive lipid through hydrolysis of sn-1 fatty acids on phosphatidylserine (PS). PLA1A has been associated with cancer metastasis, asthma, as well as acute coronary syndrome. However, the functions of PLA1A in the development of systemic autoimmune rheumatic diseases remain elusive. To investigate the possible implication of PLA1A during rheumatic diseases, we monitored PLA1A in synovial fluids from patients with rheumatoid arthritis and plasma of early-diagnosed arthritis (EA) patients and clinically stable systemic lupus erythematosus (SLE) patients. We used human primary fibroblast-like synoviocytes (FLSs) to evaluate the PLA1A-induced biological responses. Our results highlighted that the plasma concentrations of PLA1A in EA and SLE patients were elevated compared to healthy donors. High concentrations of PLA1A were also detected in synovial fluids from rheumatoid arthritis patients compared to those from osteoarthritis (OA) and gout patients. The origin of PLA1A in FLSs and the arthritic joints remained unknown, as healthy human primary FLSs does not express the PLA1A transcript. Besides, the addition of recombinant PLA1A stimulated cultured human primary FLSs to secrete IL-8. Preincubation with heparin, autotaxin (ATX) inhibitor HA130 or lysophosphatidic acid (LPA) receptor antagonist Ki16425 reduced PLA1A-induced-secretion of IL-8. Our data suggested that FLS-associated PLA1A cleaves membrane-exposed PS into lysoPS, which is subsequently converted to LPA by ATX. Since primary FLSs do not express any lysoPS receptors, the data suggested PLA1A-mediated pro-inflammatory responses through the ATX-LPA receptor signaling axis.

Keywords: arthritis; autotaxin; chemokines; inflammation; lyso-phosphatidylserine; lyso-phospholipid; lysophosphatidic acid; phosphatidylserine-specific phospholipase A1.

MeSH terms

  • Arthritis / genetics
  • Arthritis / immunology
  • Arthritis / metabolism
  • Arthritis / pathology*
  • Case-Control Studies
  • Female
  • Fibroblasts / immunology
  • Fibroblasts / metabolism
  • Fibroblasts / pathology*
  • Gout / genetics
  • Gout / immunology
  • Gout / metabolism
  • Gout / pathology*
  • Humans
  • Lupus Erythematosus, Systemic / genetics
  • Lupus Erythematosus, Systemic / immunology
  • Lupus Erythematosus, Systemic / metabolism
  • Lupus Erythematosus, Systemic / pathology*
  • Male
  • Phospholipases A1 / genetics
  • Phospholipases A1 / metabolism*
  • Phosphoric Diester Hydrolases / genetics
  • Phosphoric Diester Hydrolases / metabolism*
  • Receptors, Lysophosphatidic Acid / genetics
  • Receptors, Lysophosphatidic Acid / metabolism*
  • Synovial Fluid / immunology
  • Synovial Fluid / metabolism
  • Synoviocytes / immunology
  • Synoviocytes / metabolism
  • Synoviocytes / pathology*

Substances

  • Receptors, Lysophosphatidic Acid
  • PLA1A protein, human
  • Phospholipases A1
  • Phosphoric Diester Hydrolases
  • alkylglycerophosphoethanolamine phosphodiesterase