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

• Published in: Science signaling Vol. 12; no. 563
• Main 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
• Format: Journal Article
• Language: English
• Published: United States 08-01-2019
• Subjects: 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
• ISSN: 1937-9145
• DOI: 10.1126/scisignal.aat9900

Chronic, sustained inflammation underlies many pathological conditions, including neurodegenerative diseases. Divalent manganese (Mn
) exposure can stimulate neurotoxicity by increasing inflammation. In this study, we examined whether Mn
activates the multiprotein NLRP3 inflammasome complex to promote neuroinflammation. Exposing activated mouse microglial cells to Mn
substantially augmented NLRP3 abundance, caspase-1 cleavage, and maturation of the inflammatory cytokine interleukin-1β (IL-1β). Exposure of mice to Mn
had similar effects in brain microglial cells. Furthermore, Mn
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.