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Th17 Cells Induce Dopaminergic Neuronal Death via LFA-1/ICAM-1 Interaction in a Mouse Model of Parkinson’s Disease

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Abstract

T helper (Th)17 cells, a subset of CD4+ T lymphocytes, have strong pro-inflammatory property and appear to be essential in the pathogenesis of many inflammatory diseases. However, the involvement of Th17 cells in Parkinson’s disease (PD) that is characterized by a progressive degeneration of dopaminergic (DAergic) neurons in the nigrostriatal system is unclear. Here, we aimed to demonstrate that Th17 cells infiltrate into the brain parenchyma and induce neuroinflammation and DAergic neuronal death in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)- or 1-methyl-4-phenylpyridinium (MPP+)-induced PD models. Blood–brain barrier (BBB) disruption in the substantia nigra (SN) was assessed by the signal of FITC-labeled albumin that was injected into blood circulation via the ascending aorta. Live cell imaging system was used to observe a direct contact of Th17 cells with neurons by staining these cells using the two adhesion molecules, leukocyte function-associated antigen (LFA)-1 and intercellular adhesion molecule (ICAM)-1, respectively. Th17 cells invaded into the SN where BBB was disrupted in MPTP-induced PD mice. Th17 cells exacerbated DAergic neuronal loss and pro-inflammatory/neurotrophic factor disorders in MPP+-treated ventral mesencephalic (VM) cell cultures. A direct contact of LFA-1-stained Th17 cells with ICAM-1-stained VM neurons was dynamically captured. Either blocking LFA-1 in Th17 cells or blocking ICAM-1 in VM neurons with neutralizing antibodies abolished Th17-induced DAergic neuronal death. These results establish that Th17 cells infiltrate into the brain parenchyma of PD mice through lesioned BBB and exert neurotoxic property by promoting glial activation and importantly by a direct damage to neurons depending on LFA-1/ICAM-1 interaction.

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Acknowledgements

This work was supported by grants 81271323 and 31371182 from the National Natural Science Foundation of China, MS12015104 and MS12015096 from the Nantong Applied Research Program of China, and a project funded by the Priority Academic Program Development (PAPD) of Jiangsu Higher Education Institutions.

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Authors and Affiliations

  1. Department of Physiology, School of Medicine, and Co-innovation Center of Neuroregeneration, Nantong University, 19 Qixiu Road, Nantong, Jiangsu Province, 226001, China

    Zhan Liu, Yan Huang, Bei-Bei Cao, Yi-Hua Qiu & Yu-Ping Peng

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  1. Zhan Liu
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  2. Yan Huang
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  3. Bei-Bei Cao
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  4. Yi-Hua Qiu
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Correspondence to Yi-Hua Qiu or Yu-Ping Peng.

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All animal procedures were in accordance with the National Institutes of Health guidelines and were approved by the Institutional Animal Care and Use Committee of Nantong University.

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The authors declare that they have no conflict of interest.

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Liu, Z., Huang, Y., Cao, BB. et al. Th17 Cells Induce Dopaminergic Neuronal Death via LFA-1/ICAM-1 Interaction in a Mouse Model of Parkinson’s Disease. Mol Neurobiol 54, 7762–7776 (2017). https://doi.org/10.1007/s12035-016-0249-9

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