Fatty Acid Chain Length Drives Lysophosphatidylserine-dependent Immunological Outputs

Overview

Journal Cell Chem Biol

Publisher Cell Press

Specialty Biochemistry

Date 2021 Feb 11

PMID 33571455

Citations 13

Authors

Neha Khandelwal

Minhaj Shaikh

Amol Mhetre

Shubham Singh

Theja Sajeevan

Alaumy Joshi

Kithiganahalli Narayanaswamy Balaji

Harinath Chakrapani

Siddhesh S Kamat

Affiliations

Soon will be listed here.

Abstract

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.

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