Infiltrating Peripheral Monocyte TREM-1 Mediates Dopaminergic Neuron Injury in Substantia Nigra of Parkinson's Disease Model Mice

Abstract

Abstract Background Neuroinflammation is a crucial factor in the pathogenesis of Parkinson's disease (PD). Activated microglia in the central nervous system (CNS) and peripherally infiltrating immune cells contribute to the degeneration of dopaminergic neurons. However, how the peripheral immune system leads to neuron loss and whether blocking this response slows disease progression remain largely unknown. Triggering receptor expressed on myeloid cells-1 (TREM-1), a key regulator of inflammation, plays a significant role in the pathogenesis of infection and noninfection-related inflammation. However, the specific role of TREM-1 in PD has not yet been determined. Therefore, the aim of this study was to determine the immune regulation mechanism of monocyte TREM-1 on dopaminergic neurons and motor function in PD. Methods First, we evaluated TREM-1 expression and monocyte infiltration in the substantia nigra pars compacta (SNpc) in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP)-related neurotoxic model of PD by western blot, qRT-PCR, and flow cytometry. Second, we determined the level of TREM-1 and the extent of dopaminergic neuronal injury in the SNpc after the depletion of peripheral monocytes. Motor function was assessed by the open field test, pole test, and rotarod test. Third, to determine the actual role of TREM-1 in the PD, we analyzed the effects of TREM-1 inhibition on monocytes infiltration. Assays examining dopaminergic neuron degeneration and neuroinflammation include immunofluorescence, western blot, and qRT-PCR. To corroborate the dopaminergic terminal loss in the striatum we quantified the concentration of dopamine in the striatum using High-performance liquid chromatography (HPLC). Additionally, we conducted an adoptive transfer of TREM-1-producing monocytes from PD model mice to investigate whether monocytes induce dopaminergic neuron injury and motor dysfunction in a TREM-1-dependent manner. Results MPTP administration successfully induced subacute PD model and increased peripheral blood inflammatory monocyte levels. Deletion of peripheral monocytes protected against MPTP neurotoxicity in the SNpc. TREM-1 inhibition genetically or pharmacologically dampens the peripheral innate response, reduces the accumulation of infiltrating monocytes, and efficiently prevents dopaminergic neuron injury in the SNpc. Adoptive transfer of TREM-1-producing monocytes from PD model mice was sufficient to induce dopaminergic neurons and motor deficits in naive mice. Conclusion These results indicate the critical role of peripheral monocytes in the pathogenesis of PD and suggest that inhibiting monocyte TREM-1 expression is a promising therapeutic approach for the degeneration of dopaminergic neurons in the SNpc in PD patients.