Mn+2 Activates NLRP3 Inflammasome Signaling, Propagates Exosomal Release of Inflammasome Adaptor Protein ASC in Microglial Cells; Welders Exposed to Manganese-Containing Fumes Had Plasma Exosomes with More ASC Than Controls; Association with Parkinson’s

Researchers from Iowa State University (ISU) and Penn State Health Milton S. Hershey Medical Center have reported work showing that manganese activates NLRP3 inflammasome signaling and propagates exosomal release of inflammasome adaptor protein ASC [apoptosis-associated speck-like protein containing CARD)]in microglial cells. Their article was published online on January 8, 2019, in Science Signaling. At the outset, the scientists, led by senior author Anumantha G. Kanthasamy, PhD, ISU Chair of Biomedical Sciences & Eminent Scholar in Veterinary Medicine, state that chronic occupational exposure to manganese is associated with the development of Parkinson’s disease. They note that others had earlier found that exposure of primed microglial cells or mice to manganese increased NLRP3 inflammasome expression and activation. Manganese caused mitochondrial dysfunction in treated microglial cells and stimulated their release of exosomes containing the inflammasome adaptor protein ASC. The effects of manganese on inflammasome activation were sensitive to reduced endocytosis and transferable by exposure of cells to purified exosomes from ASC-sufficient cells. Similarly, serum exosomes from welders contained more ASC protein and were more inflammatory than those from normal donors, suggesting that occupational manganese exposure may increase systemic inflammasome activation due to exosome-mediated transfer of ASC. The authors note that chronic, sustained inflammation underlies many pathological conditions, including neurodegenerative diseases, and that divalent manganese (Mn2+) exposure can stimulate neurotoxicity by increasing inflammation. In the current study, the researchers examined whether Mn2+ activates the multiprotein NLRP3* inflammasome complex to promote neuroinflammation.
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