TREM-1 mediates interaction between substantia nigra microglia and peripheral neutrophils
Tong Shen, Guiyun Cui, Hao Chen, Long Huang, Weihong Song, Jie Zu, Wei Zhang, Chuanying Xu, Liguo Dong, Yongmei Zhang
Abstract
Abstract JOURNAL/nrgr/04.03/01300535-202406000-00043/inline-graphic1/v/2025-09-25T172020Z/r/image-tiff Microglia-mediated neuroinflammation is considered a pathological feature of Parkinson’s disease. Triggering receptor expressed on myeloid cell-1 (TREM-1) can amplify the inherent immune response, and crucially, regulate inflammation. In this study, we found marked elevation of serum soluble TREM-1 in patients with Parkinson’s disease that positively correlated with Parkinson’s disease severity and dyskinesia. In a mouse model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson’s disease, we found that microglial TREM-1 expression also increased in the substantia nigra. Further, TREM-1 knockout alleviated dyskinesia in a mouse model of Parkinson’s disease and reduced dopaminergic neuronal injury. Meanwhile, TREM-1 knockout attenuated the neuroinflammatory response, dopaminergic neuronal injury, and neutrophil migration. Next, we established an in vitro 1-methyl-4-phenyl-pyridine-induced BV2 microglia model of Parkinson’s disease and treated the cells with the TREM-1 inhibitory peptide LP17. We found that LP17 treatment reduced apoptosis of dopaminergic neurons and neutrophil migration. Moreover, inhibition of neutrophil TREM-1 activation diminished dopaminergic neuronal apoptosis induced by lipopolysaccharide. TREM-1 can activate the downstream CARD9/NF-κB proinflammatory pathway via interaction with SYK. These findings suggest that TREM-1 may play a key role in mediating the damage to dopaminergic neurons in Parkinson’s disease by regulating the interaction between microglia and peripheral neutrophils.