Dectin-1 participates in neuroinflammation and dopaminergic neurodegeneration through synergistic signaling crosstalk with TLR4

Abstract

Neuroinflammation mediated by microglial activation plays a prominent role in the pathogenesis of Parkinson’s disease (PD). Dendritic cell-associated C-type lectin-1 (Dectin-1) is a pattern recognition receptor that is involved in innate immunity. However, the role of Dectin-1 on dopaminergic neuronal damage remains unclear. Our results demonstrated that the expression of Dectin-1 was significantly increased in the microglia of the LPS-induced PD mouse model. Inhibition of Dectin-1 by laminarin (LAM) attenuated LPS-induced dopaminergic neuronal damage in substantia nigra (SN) and behavioral deficits and promoted the phenotypic transformation of microglia from M1 to M2. Moreover, inhibition or knockdown of Dectin-1 significantly decreased LPS-induced phosphorylation of Syk and P65 as well as the production of COX-2 and iNOS in BV2 cells. Knockdown of Syk also significantly decreased LPS-induced protein expressions of COX-2 and iNOS. Mechanistically, both TLR4 inhibitor and NF-κB inhibitor could antagonize LPS-induced Dectin-1 expression. Chromatin immunoprecipitation (ChIP) assays showed a physical binding of NF-κB/P65 to Dectin-1 promoter, which further indicated the regulatory effect of toll-like receptor 4 (TLR4)/NF-κB signaling pathway on Dectin-1 expression. Furthermore, the present study provided the first evidence that Dectin-1 activation by hot-alkali treated depleted zymosan (d-Zymosan) could induce dopaminergic neurotoxicity and motor dysfunction, and promote up-regulation of TLR4, iNOS and Iba-1 in C57BL/6J mice. In conclusion, Dectin-1-Syk synergistic signaling crosstalk with TLR4/NF-κB promotes and maintains inflammatory phenotypes of M1 microglia which induces dopaminergic neuronal damage in SN. These findings provide novel insights into the pivotal role of Dectin-1 in neuroinflammation, suggesting its potential as a novel therapeutic target for PD.