RANTES-induced invasion of Th17 cells into substantia nigra potentiates dopaminergic cell loss in MPTP mouse model of Parkinson's disease

Abstract

Although Parkinson's disease (PD) is a progressive neurodegenerative disease, the disease does not progress or persist in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model, the most common animal model of PD. Recently, we have described that supplementation of regulated on activation, normal T cell expressed and secreted (RANTES), a chemokine known to drive infiltration of T cells, induces persistent nigrostriatal pathology in MPTP mouse model. However, which particular T cell subsets are recruited to the substantia nigra (SN) by RANTES is not known. Here, by adoptive transfer of different subset of T cells from tomato red transgenic mice to MPTP-intoxicated immunodeficient Rag1−/− mice, we describe that invasion of Th17 cells into the SN is stimulated by exogenous RANTES administration. On the other hand, RANTES supplementation remained unable to influence the infiltration of Th1 and Tregs into the SN of MPTP-insulted Rag1−/− mice. Accordingly, RANTES supplementation increased MPTP-induced TH cell loss in Rag1−/−mice receiving Th17, but neither Th1 nor Tregs. RANTES-mediated aggravation of nigral TH neurons also paralleled with significant DA loss in striatum and locomotor deficits in MPTP-intoxicated Rag1−/− mice receiving Th17 cells. Finally, we demonstrate that levels of IL-17 (a Th17-specific cytokine) and RANTES are higher in serum of PD patients than age-matched controls and that RANTES positively correlated with IL-17 in serum of PD patients. Together, these results highlight the importance of RANTES-Th17 pathway in progressive dopaminergic neuronal loss and associated PD pathology.