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.
All Science Journal Classification (ASJC) codes
- Molecular Biology
- Cell Biology