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Publication Detail

Title: Manganese activates NLRP3 inflammasome signaling and propagates exosomal release of ASC in microglial cells.

Authors: Sarkar, Souvarish; Rokad, Dharmin; Malovic, Emir; Luo, Jie; Harischandra, Dilshan S; Jin, Huajun; Anantharam, Vellareddy; Huang, Xuemei; Lewis, Mechelle; Kanthasamy, Arthi; Kanthasamy, Anumantha G

Published In Sci Signal, (2019 01 08)

Abstract: Chronic, sustained inflammation underlies many pathological conditions, including neurodegenerative diseases. Divalent manganese (Mn2+) exposure can stimulate neurotoxicity by increasing inflammation. In this study, we examined whether Mn2+ activates the multiprotein NLRP3 inflammasome complex to promote neuroinflammation. Exposing activated mouse microglial cells to Mn2+ substantially augmented NLRP3 abundance, caspase-1 cleavage, and maturation of the inflammatory cytokine interleukin-1β (IL-1β). Exposure of mice to Mn2+ had similar effects in brain microglial cells. Furthermore, Mn2+ impaired mitochondrial ATP generation, basal respiratory rate, and spare capacity in microglial cells. These data suggest that Mn-induced mitochondrial defects drove the inflammasome signal amplification. We found that Mn induced cell-to-cell transfer of the inflammasome adaptor protein ASC in exosomes. Furthermore, primed microglial cells exposed to exosomes from Mn-treated mice released more IL-1β than did cells exposed to exosomes from control-treated animals. We also observed that welders exposed to manganese-containing fumes had plasma exosomes that contained more ASC than did those from a matched control group. Together, these results suggest that the divalent metal manganese acts as a key amplifier of NLRP3 inflammasome signaling and exosomal ASC release.

PubMed ID: 30622196 Exiting the NIEHS site

MeSH Terms: Animals; CARD Signaling Adaptor Proteins/metabolism*; Caspase 1/metabolism; Cells, Cultured; Exosomes/metabolism*; Inflammasomes/metabolism*; Interleukin-1beta/metabolism; Male; Manganese/pharmacology*; Mice, Inbred C57BL; Microglia/drug effects*; Microglia/metabolism; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism*; Signal Transduction/drug effects*; Welding

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