TY - JOUR
T1 - Manganese activates NLRP3 inflammasome signaling and propagates exosomal release of ASC in microglial cells
AU - Sarkar, Souvarish
AU - Rokad, Dharmin
AU - Malovic, Emir
AU - Luo, Jie
AU - Harischandra, Dilshan S.
AU - Jin, Huajun
AU - Anantharam, Vellareddy
AU - Huang, Xuemei
AU - Lewis, Mechelle
AU - Kanthasamy, Arthi
AU - Kanthasamy, Anumantha G.
N1 - Publisher Copyright:
Copyright © 2019 The Authors, some rights reserved;
PY - 2019/1/8
Y1 - 2019/1/8
N2 - Chronic, sustained inflammation underlies many pathological conditions, including neurodegenerative diseases. Divalent manganese (Mn 2+ ) exposure can stimulate neurotoxicity by increasing inflammation. In this study, we examined whether Mn 2+ activates the multiprotein NLRP3 inflammasome complex to promote neuroinflammation. Exposing activated mouse microglial cells to Mn 2+ substantially augmented NLRP3 abundance, caspase-1 cleavage, and maturation of the inflammatory cytokine interleukin-1 (IL-1). Exposure of mice to Mn 2+ had similar effects in brain microglial cells. Furthermore, Mn 2+ 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-1 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.
AB - Chronic, sustained inflammation underlies many pathological conditions, including neurodegenerative diseases. Divalent manganese (Mn 2+ ) exposure can stimulate neurotoxicity by increasing inflammation. In this study, we examined whether Mn 2+ activates the multiprotein NLRP3 inflammasome complex to promote neuroinflammation. Exposing activated mouse microglial cells to Mn 2+ substantially augmented NLRP3 abundance, caspase-1 cleavage, and maturation of the inflammatory cytokine interleukin-1 (IL-1). Exposure of mice to Mn 2+ had similar effects in brain microglial cells. Furthermore, Mn 2+ 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-1 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.
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U2 - 10.1126/scisignal.aat9900
DO - 10.1126/scisignal.aat9900
M3 - Article
C2 - 30622196
AN - SCOPUS:85059795691
SN - 1945-0877
VL - 12
JO - Science signaling
JF - Science signaling
IS - 563
M1 - aat9900
ER -