Role of Parkin in innate immunity: crosstalk between mitochondrial dysfunction and NLRP3 inflammasome signaling

Abstract

Mitochondrial dysfunction and chronic neuroinflammation are central mechanisms in the pathogenesis of Parkinson’s disease (PD). Studies provided evidence that microglial overactivation of the NLRP3-inflammasome, a signaling complex that senses reactions to tissue damage, contributes to neurodegeneration in PD. The PD-linked gene PARK2/Parkin plays a central role in the regulation of mitochondrial quality control. Recent links have been established between mitochondria, Parkin and innate immunity responses. The objective of this project was to determine to what extent and by which mechanisms Parkin deficiency and mitochondrial dysfunction affect microglial response to pro-inflammatory stimuli and inflammasome activation. Cells from WT and Park2-knockout mice were obtained using an innovative in house protocol for the isolation of highly enriched microglia and then exposed to specific inducers of the NLRP3-inflammasome (nigericin…). Microglial activation was evaluated by measuring morphological changes and cytokines production. Our results show that Parkin deficiency exacerbates the increase in NLRP3 levels and IL-1β release triggered by nigericin in microglial cells, accompanied by corresponding morphological changes. This hyperactivaton profile was reversed by the selective inhibitor of NLRP3-inflammasome complex formation, MCC950. This work will foster integrated consideration of the deleterious crosstalk between these two key pathological mechanisms underlying PD in animal models and patients.