The role of Nurr1-miR-30e-5p-NLRP3 axis in inflammation-mediated neurodegeneration: insights from mouse models and patients’ studies in Parkinson’s disease

作者：Tianbai Li, Xiang Tan, Lulu Tian, Congcong Jia, Cheng Cheng, Xi Chen, Min Wei, Yuanyuan Wang, Yiying Hu, Qiqi Jia, Yang Ni, Murad Al‐Nusaif, Song Li, Weidong Le · 发表于：Journal of Neuroinflammation · 年份：2023 · DOI：10.1186/s12974-023-02956-x · 被引用次数：24 · 研究领域：Nuclear Receptors and Signaling、RNA regulation and disease、RNA Interference and Gene Delivery

Abstract Nuclear receptor related-1 (Nurr1), a ligand-activated transcription factor, is considered a potential susceptibility gene for Parkinson’s disease (PD), and has been demonstrated to possess protective effects against inflammation-induced neuronal damage. Despite the evidence showing decreased NURR1 level and increased pro-inflammatory cytokines in cell and animal models as well as in PD patients’ peripheral blood mononuclear cells (PBMCs), the underlying mechanism remains elusive. In this study, we investigated the molecular mechanism of Nurr1 in PD-related inflammation. Through the miRNA-sequencing and verification in PBMCs from a cohort of 450 individuals, we identified a significant change of a Nurr1-dependent miRNA miR-30e-5p in PD patients compared to healthy controls (HC). Additionally, PD patients exhibited an elevated plasma interleukin-1β (IL-1β) level and increased nucleotide-binding domain-like receptor protein 3 (NLRP3) expression in PBMCs compared to HC. Statistical analyses revealed significant correlations among NURR1 , miR-30e-5p, and NLRP3 levels in the PBMCs of PD patients. To further explore the involvement of Nurr1-miR-30e-5p-NLRP3 axis in the inflammation-mediated PD pathology, we developed a mouse model (Nurr1 flox+/Cd11b−cre+ , Nurr1 cKO ) conditionally knocking out Nurr1 in Cd11b-expressing cells. Our investigations in Nurr1 cKO mice unveiled significant dopaminergic neurodegeneration following lipopolysaccharide-induced inflammation. Remarkab...