CCL5 Promotes LFA-1 Expression in Th17 Cells and Induces LCK and ZAP70 Activation in a Mouse Model of Parkinson’s Disease

Background: Parkinson's disease (PD), the second most common neurodegenerative disease, is characterized by the pathological deposition of alpha-synuclein (α-Syn) and loss of dopaminergic (DA) neurons. Th17 cells are considered to be responsible for the direct loss of DA neurons. C-C chemokine ligand 5 (CCL5) specifically induces Th17 cell infiltration in the substantia nigra (SN). However, the specific effect of CCL5 on Th17 cells in PD and the relationship between CCL5 and lymphocyte function-associated antigen-1 (LFA-1) expression in Th17 cells have not been clarified. Methods: We evaluated the effects of CCL5 on LFA-1 expression in Th17 cells in mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Moreover, we examined Th17 cell differentiation upon CCL5 stimulation in vitro. Furthermore, we assessed the effects of CCL5 on tyrosine kinase zeta-chain-associated protein kinase 70 (ZAP70) and lymphocyte-specific protein tyrosine kinase (LCK) activity in CCL5-stimulated Th17 cells in vivo and in vitro. Results: CCL5 increased the proportion of peripheral Th17 cells in MPTP-treated mice, LFA-1 expression on Th17 cells, and the number of Th17 cells in the SN of MPTP-treated mice. Additionally, CCL5 promoted Th17 cell differentiation and LFA-1 expression in naive T cells cultured in vitro. Moreover, CCL5 increased the differentiation of Th17 cells and the expression of LFA-1 by stimulating LCK and ZAP70 activation in naïve CD4 + T cells. Furthermore, inhibiting LCK and ZAP70 activation reduced the proportion of peripheral Th17 cells and surface expression of LFA-1 in MPTP-treated mice, and the number of Th17 cells in the SN was also significantly decreased. Conclusion: CCL5, which could increase the differentiation of Th17 cells and LFA-1 protein expression by activating LCK and ZAP70, could increase Th17 cells in the SN, induce the death of DA neurons and aggravate PD.