Fatty acid chain length drives lysophosphatidylserine-dependent immunological outputs

Khandelwal, N and Shaikh, M and Mhetre, A and Singh, S and Sajeevan, T and Joshi, A and Balaji, KN and Chakrapani, H and Kamat, SS (2021) Fatty acid chain length drives lysophosphatidylserine-dependent immunological outputs. In: Cell Chemical Biology .

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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. 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. © 2021 Elsevier Ltd

Item Type:	Journal Article
Publication:	Cell Chemical Biology
Publisher:	Elsevier Ltd
Additional Information:	The copyright for this article belongs to Elsevier Ltd
Department/Centre:	Division of Biological Sciences > Microbiology & Cell Biology
Date Deposited:	17 Mar 2021 10:29
Last Modified:	17 Mar 2021 10:29
URI:	http://eprints.iisc.ac.in/id/eprint/68404

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