Objective: To explore the specific pathway by which CCL5 induces Th17 cells migrating into substantia nigra pars compacta (SNpc) to aggravate Parkinson’s disease (PD).

Background: It is proven that the concentration of C-C chemokine ligand 5 (CCL5) in blood increases in PD, and there is a strong correlation between serum CCL5 levels and severity of the PD (UPDRS-III scores). Additionally, CCL5 can induce Th17 into SNpc, which can increase dopaminergic cell loss in MPTP mouse model of PD, Understanding the specific mechanism of CCL5 action on Th17 is the key to protect dopamine neurons and postpone the progression of PD.

Method: We randomly divided twelve C57 mice into four groups for modeling in the animal experiments. The mice were treated with PBS, MPTP (acute model, 20mg/kg, 4 times/day), PBS+CCL5 (injected on the third and sixth day after PBS injection, 5ug/kg per time) and MPTP+CCL5, respectively. All mice were sacrificed, and their spleen tissues were collected for flow cytometry to observe the effect of CCL5 on Th17. The SNpc were collected for Immunofluorescence, Western blot and qPCR to detect the death of dopamine neurons and SNpc migration of Th17 cells in vivo. On the other hand, we performed magnetic bead sorting on spleen cells of WT mice for cells experiments. Naïve T cells were isolated and cultured in vitro to induce differentiation toward Th17. PBS and CCL5 were added respectively. We collected the cells on the third day to observe the effects of CCL5 on the differentiation and function of Th17 cells.

Results: Our study found that CCL5 could promote the migration of Th17 into SNpc, which could lead to the death of dopamine neurons. We also found that more Th17 in the MPTP+CCL5 group migrate to SNpc than those in the MPTP model of PD, which resulted in the loss of more dopamine neurons. Current study also showed that CCL5 promoted the increase of Th17 and LFA-1 ratio, as well as Th17 could use LFA-1 to migrate into SNpc. The results that CCL5 could accelerate the increase of Th17 and LFA-1 were also confirmed in the cell experiments.

Conclusion: CCL5 will promote the proportion of Th17 cells and increase the expression of LFA-1 on Th17 surface. These results are helpful for Th17 to migrate into SNpc, induce the death of dopamine neurons and aggravate PD progression. However, the specific pathway of CCL5 on Th17 needs further study in the future.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/ccl5-promotes-th17-migrating-into-snpc-by-promoting-th17-proportion-increase-and-lfa-1-expression/