Details

Autor(en) / Beteiligte

• Kondru, Naveen
• Manne, Sireesha
• Hepker, Monica
• Malovic, Emir
• Jin, Huajun
• Anantram, Vellareddy
• Kanthasamy, Arthi
• Kanthasamy, Anumantha G

Titel

Manganese exposure augments misfolded α‐synuclein‐induced proinflammatory M1 microglial phenotype and inflammasome activation

Ist Teil von

• The FASEB journal, 2019-04, Vol.33 (S1), p.505.7-505.7

Ort / Verlag

The Federation of American Societies for Experimental Biology

Erscheinungsjahr

2019

Quelle

Wiley Online Library

Beschreibungen/Notizen

• Sustained microglial activation is a key player in the immunopathogenesis of several neurodegenerative disorders including Parkinson's disease (PD). Chronic exposure to the environmental toxicant manganese (Mn) has been implicated as a risk factor for PD. We have previously demonstrated that misfolded and aggregated human α‐synuclein (αSynPFF) induces microglial activation. Recently, we have shown that chronic Mn exposure induces neuroinflammation by impairing mitochondrial dynamics. In this study, we determined whether Mn exposure alters the specific RNA transcripts in response to the αSynPFF proteostatic challenge. We systematically characterized the transcriptome of mouse microglia in response to Mn and/or αSynPFF using RNA sequencing. Treating a mouse microglial cell model with αSynPFF significantly induced both cytokine and interferon‐g signaling pathways. In contrast, Mn treatment caused distinct changes to pathways related to cellular senescence and apoptosis. Intriguingly, co‐treatment with Mn and αSynPFF caused profound enrichment of transcripts, including IL‐6, IL‐12b, IFN‐β, IL‐1α, and IL‐1β CXCL2, CXCL3, CXCL10, CCL5‐R, and Nos2, that signify the proinflammatory M1 microglial phenotype. These targets were further validated by real‐time qRT‐PCR, immunoblotting, and immunocytochemistry. As anticipated, cotreatment with Mn and αSynPFF lead to significant upregulation of the mRNA expression of IL‐6, Nos2, IL‐1α, and IL‐1β in a synergistic manner when compared to either treatment alone. Additionally, Mn and αSynPFF co‐treatment elicited NLRP3 inflammasome activation when compared to either treatment alone or untreated control cells. Taken together, these findings identify that environmental toxicants, such as Mn, perturb microglial homeostasis, thereby leading to transformation to a pro‐inflammatory M1 microglial phenotypic state. Importantly, our study suggests that the environmental toxicant Mn can augment αSynPFF‐induced neuroinflammatory processes in microglia to accelerate neurodegeneration. Support or Funding Information NIH grants ES026892, NS088206, and W. Eugene Linda Lloyd Endowed Chair This is from the Experimental Biology 2019 Meeting. There is no full text article associated with this published in The FASEB Journal.