α‐Synuclein evokes NLRP3 inflammasome‐mediated IL‐1β secretion from primary human microglia

Abstract

Synucleinopathies such as Parkinson's disease (PD) are hallmarked by α‐synuclein (α‐syn) pathology and neuroinflammation. This neuroinflammation involves activated microglia with increased secretion of interleukin‐1β (IL‐1β). The main driver of IL‐1β secretion from microglia is the NLRP3 inflammasome. A critical link between microglial NLRP3 inflammasome activation and the progression of both α‐syn pathology and dopaminergic neurodegeneration has been identified in various PD models in vivo. α‐Syn is known to activate the microglial NLRP3 inflammasome in murine models, but its relationship to this inflammasome in human microglia has not been established. In this study, IL‐1β secretion from primary mouse microglia induced by α‐syn fibrils was dependent on NLRP3 inflammasome assembly and caspase‐1 activity, as previously reported. We show that exposure of primary human microglia to α‐syn fibrils also resulted in significant IL‐1β secretion that was dependent on inflammasome assembly and involved the recruitment of caspase‐1 protein to inflammasome scaffolds as visualized with superresolution microscopy. While canonical IL‐1β secretion was clearly dependent on caspase‐1 enzymatic activity, this activity was less clearly involved for α‐syn‐induced IL‐1β secretion from human microglia. This work presents similarities between primary human and mouse microglia in the mechanisms of activation of the NLRP3 inflammasome by α‐syn, but also highlights evidence to suggest that there may be a difference in the requirement for caspase‐1 activity in IL‐1β output. The data represent a novel characterization of PD‐related NLRP3 inflammasome activation in primary human microglia and further implicate this mechanism in the pathology underlying PD.

Targeting Microglial α-Synuclein/TLRs/NF-kappaB/NLRP3 Inflammasome Axis in Parkinson’s Disease

“…The above-mentioned studies are predominantly based on animal models. Recently, a-syn was reported to activate NLRP3 in human primary microglia, and induce NLRP3-dependent caspase-1-mediated secretion of IL-1b (88). Furthermore, a-syn aggregates activated NLRP3 by binding to TLR2, but not TLR4 in human induced pluripotent stem cell (hiPSC)-derived microglia (hiMG).…”

PKC Delta Activation Promotes Endoplasmic Reticulum Stress (ERS) and NLR Family Pyrin Domain-Containing 3 (NLRP3) Inflammasome Activation Subsequent to Asynuclein-Induced Microglial Activation: Involvement of Thioredoxin-Interacting Protein (TXNIP)/Thioredoxin (Trx) Redoxisome Pathway

“…Lewy bodies, which represent a classical pathological hallmark of PD and DLB exhibits microglial and neuronal inclusions enriched with αSyn agg (Fellner et al, 2011;Hoffmann et al, 2019). Given that αSyn agg positive inclusions appear prior to the development of clinical signs (Braak et al, 2006) and that they are taken up by the microglia and contribute to the templated conversion of endogenous monomeric αSyn (Earls et al, 2019;Pike et al, 2021). We initially characterized the αSyn fibrils.…”

iPSC-Derived Microglia as a Model to Study Inflammation in Idiopathic Parkinson’s Disease

“…The priming signal is characterized by the upregulation of IL1B and NLRP3 expression, while the secondary signal is characterized by the release of mature cytokines (Swanson et al, 2019). Underlining the relevance of the NLRP3 inflammasome, IL-1β has been associated with disease pathogenesis in multiple PD biomarker studies (Koprich et al, 2008;Su et al, 2008;Nakahira et al, 2011;Gillardon et al, 2012;Pike et al, 2021).…”