GPR120 exacerbates the immune-inflammatory response in chicken liver by mediating acetochlor induced macrophage M1 polarization

Abstract

Acetochlor is a widely used and highly effective herbicide. Its overuse poses significant threats to biosecurity and ecological integrity, particularly affecting free-ranging birds. Data on its impact, especially mechanisms of liver toxicity in chickens, are lacking. Thus, we established an animal-cell-animal model to explore intrinsic mechanisms at multiple levels. We found that acetochlor exposure caused liver cell swelling, inflammatory cell accumulation, and lipid deposition. Transcriptomic analyses revealed that differential gene were mainly enriched in hepatic immune, inflammatory, and programmed cell death pathways. We next focused on the gene GPR120, conducting transfection and agonism experiments in LMH, HD11, and co-cultured cells. Acetochlor significantly increased ROS accumulation, activated the NLRP3 inflammasome, and which induced PANoptosis. HD11 cells exhibited M1 polarization with upregulated pro-inflammatory factors. Silencing GPR120 exacerbated cellular damage and immune responses, whereas its agonist, GSK7A, dramatically reduced macrophage M1 polarization and mitigated immune damage to LMH cells. Finally, we returned to animal studies, adding Omega-3-a known GPR120 agonist-to the diet. Omega-3 effectively reversed acetochlor-induced hepatitis and PANoptosis. Given that acetochlor residues pose potential threats to ecosystems and avian health, it is crucial to strengthen residue control, conduct risk assessments, and explore targeted pathways and nutritional supplementation to counteract these negative impacts.