Fatty acid chain length drives lysophosphatidylserine-dependent immunological outputs

Cell Chem Biol. 2021 Aug 19;28(8):1169-1179.e6. doi: 10.1016/j.chembiol.2021.01.008. Epub 2021 Feb 10.


In humans, lysophosphatidylserines (lyso-PSs) are potent lipid regulators of important immunological processes. Given their structural diversity and commercial paucity, here we report the synthesis of methyl esters of lyso-PS (Me-lyso-PSs) containing medium- to very-long-chain (VLC) lipid tails. We show that Me-lyso-PSs are excellent substrates for the lyso-PS lipase ABHD12, and that these synthetic lipids are acted upon by cellular carboxylesterases to produce lyso-PSs. Next, in macrophages we demonstrate that VLC lyso-PSs orchestrate pro-inflammatory responses and in turn neuroinflammation via a Toll-like receptor 2 (TLR2)-dependent pathway. We also show that long-chain (LC) lyso-PSs robustly induce intracellular cyclic AMP production, cytosolic calcium influx, and phosphorylation of the nodal extracellular signal-regulated kinase to regulate macrophage activation via a TLR2-independent pathway. Finally, we report that LC lyso-PSs potently elicit histamine release during the mast cell degranulation process, and that ABHD12 is the major lyso-PS lipase in these immune cells.

Keywords: ABHD12; GPCR; PHARC; TLR2; lyso-PS; mast cell degranulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Fatty Acids / chemistry
  • Fatty Acids / immunology*
  • Female
  • Histamine / immunology
  • Humans
  • Lipids / chemistry
  • Lipids / immunology
  • Lysophospholipids / chemistry
  • Lysophospholipids / immunology*
  • Lysophospholipids / metabolism
  • Macrophages / immunology
  • Male
  • Mast Cells / immunology
  • Mice
  • Monoacylglycerol Lipases / metabolism
  • Substrate Specificity


  • Fatty Acids
  • Lipids
  • Lysophospholipids
  • lysophosphatidylserine
  • Histamine
  • ABHD12 protein, human
  • Monoacylglycerol Lipases