PM2.5 Exacerbates Viral Myocarditis by Disrupting Lysophosphatidylcholine Metabolism and Inhibiting the GPR4/ERK/PPARγ Pathway.

Epidemiological studies link fine particulate matter (PM2.5) exposure to aggravated viral myocarditis (VMC), though the mechanisms remain unclear. This study aimed to investigate whether PM2.5 exacerbates the inflammatory response by disrupting lysophosphatidylcholine (LPC) metabolism and its downstream signaling pathways. We established the mouse model combining PM2.5 exposure and CVB3 infection. Cardiac function, inflammation, and signaling molecule alterations were assessed using echocardiography, histological analysis, and molecular techniques. In H9c2 cardiomyocytes, we applied PM2.5, LPC, GPR4 siRNA, and pathway inhibitors (U0126 and GW9662). PM2.5 reduced LPC levels in vivo and in vitro and downregulated its receptor GPR4. It also suppressed the ERK/PPARγ pathway, thereby lifting transcriptional inhibition of Toll-like receptor 4 (TLR4). GPR4 knockdown abolished the activating effects of LPC on ERK/PPARγ and its inhibitory effect on TLR4. Our study also confirmed that ERK and PPARγ function sequentially downstream of GPR4 and upstream of TLR4 within this pathway. The study suggests a novel mechanism by which PM2.5 exacerbates VMC. PM2.5 disrupts LPC metabolism, inhibits the GPR4/ERK/PPARγ pathway, and consequently releases the inhibition on TLR4, thereby increasing cardiac susceptibility to CVB3 and inflammatory injury. This pathway represents a potential therapeutic target for preventing PM2.5-associated myocardial damage.