CXCL12 is involved in α-synuclein-triggered neuroinflammation of Parkinson’s disease

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.

CXCL-12 Attenuates Neuroinflammation via the CXCR4/PI3K/Akt Signaling Pathway in a Rat Model of SAH

“…It induces immune cell migration and nervous system development by binding to its ligand, CXCL-12. CXCR4 is involved in regulating the in ammatory response in central nervous system diseases, such as Alzheimer's disease [30], ischemic stroke [18], and Parkinson's disease [31]. In the present study, our results showed that the expression of exogenous CXCL-12 and CXCR4 increased at the early stage of SAH and peaked at 24 h after SAH.…”

Proteomics Profiling of Neuron-Derived Small Extracellular Vesicles from Human Plasma: Enabling Single-Subject Analysis

“…Clusterin has been repeatedly linked to PD, and its plasma levels have been found to be increased in PD patients [ 47 ]. Stromal cell-derived factor 1 ( CXCL12 ) was confirmed to be positively correlated with α-syn in post-mortem brains tissues of PD patients and increased in the blood of PD patients [ 27 ]; moreover, in the same study, α-syn increased the production of CXCL12 in microglia [ 48 ].…”

Cerebral sterile inflammation in neurodegenerative diseases

“…Microglial TLR4 is also activated by soluble or fibrillar α-synuclein to induce the production of inflammatory cytokines, chemokines, and ROS [ 73 ]. Among chemokines, CXCL12 is important for the accumulation of microglia activated by α-synuclein [ 74 ].…”