Details

Autor(en) / Beteiligte

• Malovic, Emir
• Sarkar, Souvarish
• Rokad, Dharmin
• Luo, Jie
• Harischandra, Dilshan
• Jin, Huajun
• Anantharam, Vellareddy
• Huang, Xuemei
• Lewis, Mechelle
• Kanthasamy, Arthi
• Kanthasamy, Anumantha

Titel

Manganese Exposure Activates NLRP3 Inflammasome Signaling and Propagates Exosomal Release of ASC in Microglial Cells

Ist Teil von

• The FASEB journal, 2018-04, Vol.32 (S1), p.823.8-823.8

Ort / Verlag

The Federation of American Societies for Experimental Biology

Erscheinungsjahr

2018

Link zum Volltext

Quelle

Wiley Blackwell Single Titles

Beschreibungen/Notizen

• Abnormal metal homeostasis is a key hallmark of multiple neurodegenerative disorders including Alzheimer's and Parkinson's diseases. Toxicological exposure to manganese (Mn) has been linked to PD‐like symptoms. Sustained neuroinflammation is now recognized as a key pathophysiological process of neurodegenerative conditions, but the inflammatory signaling mechanism underlying Mn neurotoxicity remains equivocal. Recent evidence suggests that the NLRP3 inflammasome, a multiprotein complex, can be activated by various exogenous and endogenous stimuli, leading to a chronic inflammatory response. In this study, we examined whether Mn exerts its neurotoxic effect by activating NLRP3 inflammasome signaling. Exposing LPS‐primed microglial cells to Mn significantly increased NLRP3 expression, caspase‐1 cleavage, and IL‐1β maturation, indicating that Mn can induce the NLRP3 inflammasome activation cascade. Mn exposure compromised the mitochondrial dynamics of microglial cells, as measured via Seahorse Mito Stress assay, and downregulated mitochondrial fusion. Furthermore, Mn reduced the expression of the retromer pathway protein VPS35. CRISPR/Cas9‐based knockdown of VPS35 also downregulated the mitochondrial fusion protein Mfn2 by increasing the mitochondrial ubiquitin ligase Mul1, suggesting a probable role of VPS35 in maintaining mitochondrial health. Given that the inflammasome component ASC can propagate inflammasome activation in a prionic manner, we explored whether Mn exposure induces cell‐to‐cell transfer of ASC via exosomes. Exosomes isolated from Mn‐treated, LPS‐primed microglial cells contained higher amounts of ASC, suggesting exosomal release of ASC. Supporting the role of exosomal ASC in inflammasome propagation, we found that exosomes isolated from microglial cells exposed to Mn were able to induce pro‐IL‐1β and NLRP3 expression. Importantly, we confirmed a significantly higher ASC content in exosomes collected from Mn‐exposed welders when compared to exosomes from matched control subjects. Collectively, these results demonstrate that Mn activates NLRP3 inflammasome proinflammatory signaling and exosomal ASC release from microglia to induce neurotoxicity. Support or Funding Information ES026892, NS088206, ES027245, and Endowed Lloyd Chair This is from the Experimental Biology 2018 Meeting. There is no full text article associated with this published in The FASEB Journal.