Agonism of GPR84 Attenuates Free Fatty Acid-Induced Endothelial Inflammation and Monocyte Adhesion via Gfi1/NF-κB Pathway.

BACKGROUND

Endothelial dysfunction and monocyte adhesion driven by free fatty acids (FFAs) are critical early events in atherosclerosis. Palmitate, a long-chain saturated free fatty acid, upregulated GPR84 expression. Although GPR84 is canonically activated by medium-chain FFAs, its induction under lipotoxic stress suggests a compensatory, context-dependent role. Its role in endothelial inflammation is poorly defined.

OBJECTIVES

To investigate the functional role of GPR84 activation in FFA-induced endothelial inflammation and elucidate the underlying mechanisms.

METHODS

Human aortic endothelial cells (HAECs) were challenged with palmitate (0.5 or 1 mM) in the presence or absence of the GPR84 agonists 6-OAU or ZQ-16 (each at 1 μM). Inflammatory cytokine and adhesion molecule expression were assessed by qPCR and ELISA. Monocyte adhesion was evaluated using THP-1 cells. NF-κB p65 nuclear translocation and Gfi1 expression were examined, and Gfi1 silencing was performed to assess functional relevance.

RESULTS

Palmitate increased GPR84 expression in HAECs. Treatment with GPR84 agonists significantly reduced palmitate-induced upregulation of IL-1β, TNF-α, MCP-1, VCAM-1, and ICAM-1 at both mRNA and protein levels, and attenuated THP-1 monocyte adhesion. Mechanistically, GPR84 activation inhibited NF-κB p65 nuclear translocation and preserved Gfi1 expression. Knockdown of Gfi1 abrogated the protective effects of GPR84 agonists, restoring NF-κB activation, adhesion molecule expression, and monocyte adhesion.

CONCLUSIONS

GPR84 agonism mitigates FFA-induced endothelial inflammation by restoring Gfi1 expression and suppressing NF-κB signaling, highlighting a potential therapeutic strategy for early atherosclerosis that warrants further in vivo validation.