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LPC 18:2-Driven Apoptosis In Neutrophils Is Non-Inflammatory and Lipid Raft Dependent

Saminathan, P.; Gibbons, A.; Mathews, I.; Corey, M. Y.; Logandha, A.; Rayadurgam, M.; Nadig, N.; Fang, C.; Reddy, N.; Vatanmakanian, M.; Sharma, S.

2025-12-12 immunology
10.64898/2025.12.09.693266 bioRxiv
Show abstract

Lysophosphatidylcholines (LPCs) are potent bioactive lipids whose fatty acid compositions dictate their immunomodulatory effects. Here, we delineate how unsaturated LPC 18:2 and saturated LPC 16:0 differentially regulate neutrophil survival and inflammatory programs. LPC 18:2 markedly increased reactive oxygen species (ROS) generation and caspase-3/7 activation, mitochondrial membrane depolarization, and cytochrome c release, features consistent with intrinsic apoptosis. In contrast, LPC 16:0 induced robust LDH and HMGB-1 release, indicating membrane rupture and pyroptosis-like death. Bulk RNA sequencing revealed that LPC 16:0 strongly upregulated inflammatory and cytokine gene expression. Disruption of lipid-raft integrity abolished LPC 18:2-induced ROS and apoptosis, underscoring the dependence of these effects on membrane organization. Collectively, these results identify LPC 18:2 as a non-inflammatory, mitochondria-dependent inducer of neutrophil apoptosis, whereas LPC 16:0 promotes inflammatory, lytic death programs. These findings highlight how lipid saturation determines neutrophil fate and immune tone, providing mechanistic insight into how distinct LPC species shape inflammation and tissue injury.

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