Mincle exacerbates neuroinflammation and dopaminergic neurodegeneration via synergistic crosstalk with TLR4.

Microglial activation and subsequent neuroinflammation are critically implicated in the pathogenesis and progression of Parkinson's disease (PD). Macrophage-inducible C-type lectin (Mincle) is a pivotal pattern recognition receptor that participates in the regulation of innate immune responses. Nevertheless, the functional role of Mincle in mediating dopaminergic neuronal injury in PD remains poorly defined. In the present study, we observed a marked upregulation of Mincle expression in microglia in PD mouse models. Pharmacological inhibition of Mincle via Anti-Mincle antibody treatment effectively alleviated LPS-triggered dopaminergic neuronal loss in the SN and rescued motor behavioral impairments in mice. Additionally, Mincle blockade promoted microglial phenotypic transformation, driving a shift from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype. Mechanistically, pharmacological blockade of either TLR4 or NF-κB signaling abrogated LPS-induced Mincle upregulation. Chromatin immunoprecipitation (ChIP) assays further confirmed that the NF-κB/P65 subunit directly binds to the promoter region of the Mincle, verifying that the TLR4/NF-κB signaling serves as a critical upstream regulatory pathway for Mincle expression. Notably, this study provides the first in vivo evidence that Mincle activation by a Mincle-specific agonist trehalose-6,6-dibehenate (TDB) induces robust dopaminergic neurotoxicity and motor dysfunction in C57BL/6 J mice, accompanied by significant elevations in the expression of the pro-inflammatory and microglial activation markers iNOS and CD68. Collectively, our findings demonstrate that synergistic crosstalk between the Mincle-Syk signaling cascade and the TLR4/NF-κB pathway sustains the pro-inflammatory M1 microglial phenotype, thereby triggering progressive dopaminergic neuronal damage in the SN. This study uncovers a previously unrecognized pathogenic role of Mincle in neuroinflammation-mediated neurodegeneration, highlighting Mincle as a promising novel therapeutic target for PD intervention.