Fatty acid chain length drives lysophosphatidylserine-dependent immunological outputs. Issue 8 (19th August 2021)

• Record Type: Journal Article
• Authors: Khandelwal, Neha; Shaikh, Minhaj; Mhetre, Amol; Singh, Shubham; Sajeevan, Theja; Joshi, Alaumy; Balaji, Kithiganahalli Narayanaswamy; Chakrapani, Harinath; Kamat, Siddhesh S.
• Is Part Of: Cell chemical biology. Volume 28:Issue 8(2021)
• Page Start: 1169
• Page End: 1179.e6
• Publication Date: 2021-08-19
• Subjects: lyso-PS -- ABHD12 -- TLR2 -- GPCR -- mast cell degranulation -- PHARC; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2021.01.008
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: 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. Highlights: Synthesis of methyl esters of lyso-PSs with varying lipid tails and their metabolism Very-long-chain lyso-PSs signal through TLR2 to cause neuroinflammation Role of long-chain lyso-PSs in macrophage signaling and mast cell degranulation ABHD12 is a major lyso-PS lipase in primary mast cells Abstract : Khandelwal et al. synthesize a library of methyl esters of lysophosphatidylserines (lyso-PSs) to facilitate rigorous structure-activity relationship studies, toward understanding the role played by the lipid tail of lyso-PSs in regulating the activation of macrophages and mast cell degranulation.