CXCL12 is involved in \u03b1-synuclein-triggered neuroinflammation of Parkinson\u2019s disease

Yuanyuan Li,Zhichun Chen,Aonan Zhao,Liming Lu,Xiongwei Zhu,Wenyan Kang,Liche Zhou,Ningdi Luo,Mengyue Niu,Jun Liu

doi:10.1186/s12974-019-1646-6

Yuanyuan Li, Zhichun Chen + Show 8 more

Open Access

https://doi.org/10.1186/s12974-019-1646-6

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Abstract

BackgroundThe mechanisms underlying the pathogenesis and progression of Parkinson’s disease (PD) remain elusive, but recent opinions and perspectives have focused on whether the inflammation process induced by microglia contributes to α-synuclein-mediated toxicity. Migration of microglia to the substantia nigra (SN) could precede neurodegeneration in A53T mice. We hypothesized that CXCL12 could be a mediator in the α-synuclein-induced migration of microglia.MethodsAfter establishing appropriate animal and cell culture models, we explored the relationship between α-synuclein and CXCL12 in A53T mice, primary microglia, and BV-2 cell lines. We also explored the mechanisms of these interactions and the signaling processes involved in neuroinflammation.ResultsWe confirmed the positive correlation between α-synuclein and CXCL12 in the postmortem brain tissue of PD patients and the upregulated CXCR4 expression in SN microglia of A53T mice. In addition, as expected, α-synuclein increased the production of CXCL12 in microglia via TLR4/IκB-α/NF-κB signaling. Importantly, CXCL12/CXCR4/FAK/Src/Rac1 signaling was shown to be involved in α-synuclein-induced microglial accumulation.ConclusionsOur study suggests that CXCL12 could be a novel target for the prevention of α-synuclein-triggered ongoing microglial responses. Blocking CXCL12/CXCR4 may be a potential therapeutic approach for PD progression.

Highlights

The mechanisms underlying the pathogenesis and progression of Parkinson’s disease (PD) remain elusive, but recent opinions and perspectives have focused on whether the inflammation process induced by microglia contributes to α-synuclein-mediated toxicity
We found that CXCL12 was upregulated in substantia nigra (SN) tissue from postmortem PD patients and A53T (α-synuclein mutant) mice. α-Synuclein could promote the secretion of CXCL12 by microglia via the TLR4/Inhibitor of Nuclear factor kappa (NF-κB) (IκB-α)/NF-κB pathway
CXCL12/CXCR4 was overexpressed in the brain tissues of PD patients and A53T transgenic mice As indicated by a previous study, CXCL12 and CXCR4 are upregulated in both the postmortem brain tissues of PD patients and in MPTP-treated mice [26]

Summary

Introduction

The mechanisms underlying the pathogenesis and progression of Parkinson’s disease (PD) remain elusive, but recent opinions and perspectives have focused on whether the inflammation process induced by microglia contributes to α-synuclein-mediated toxicity. The underlying pathogenetic mechanism of PD remains elusive, but recent opinions and perspectives on the subject have focused on the inflammation process induced by microglia in the SN, which contributes to α-synuclein-. Microglia have been found to preferentially colocalize with aggregated α-synuclein in the SN in PD animal models [10,11,12,13].

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