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Sarkar S, Malovic E, Harishchandra DS, et al. Mitochondrial impairment in microglia amplifies NLRP3 inflammasome proinflammatory signaling in cell culture and animal models of Parkinson's disease. NPJ Parkinsons Dis. 2017;3:30doi: 10.1038/s41531-017-0032-2.
Sarkar, S., Malovic, E., Harishchandra, D. S., Ghaisas, S., Panicker, N., Charli, A., Palanisamy, B. N., Rokad, D., Jin, H., Anantharam, V., Kanthasamy, A., & Kanthasamy, A. G. (2017). Mitochondrial impairment in microglia amplifies NLRP3 inflammasome proinflammatory signaling in cell culture and animal models of Parkinson's disease. NPJ Parkinson's disease, 330. https://doi.org/10.1038/s41531-017-0032-2
Sarkar, Souvarish, et al. "Mitochondrial impairment in microglia amplifies NLRP3 inflammasome proinflammatory signaling in cell culture and animal models of Parkinson's disease." NPJ Parkinson's disease vol. 3 (2017): 30. doi: https://doi.org/10.1038/s41531-017-0032-2
Sarkar S, Malovic E, Harishchandra DS, Ghaisas S, Panicker N, Charli A, Palanisamy BN, Rokad D, Jin H, Anantharam V, Kanthasamy A, Kanthasamy AG. Mitochondrial impairment in microglia amplifies NLRP3 inflammasome proinflammatory signaling in cell culture and animal models of Parkinson's disease. NPJ Parkinsons Dis. 2017 Oct 17;3:30. doi: 10.1038/s41531-017-0032-2. eCollection 2017. PMID: 29057315; PMCID: PMC5645400.
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NPJ Parkinsons Dis. 2017 Oct 17;3:30. doi: 10.1038/s41531-017-0032-2. eCollection 2017.

Mitochondrial impairment in microglia amplifies NLRP3 inflammasome proinflammatory signaling in cell culture and animal models of Parkinson's disease.

NPJ Parkinson's disease

Souvarish Sarkar, Emir Malovic, Dilshan S Harishchandra, Shivani Ghaisas, Nikhil Panicker, Adhithiya Charli, Bharathi N Palanisamy, Dharmin Rokad, Huajun Jin, Vellareddy Anantharam, Arthi Kanthasamy, Anumantha G Kanthasamy

Affiliations

  1. Department of Biomedical Science, Iowa State University, Ames, IA 50011 USA.
  2. Present Address: Perelman School of Medicine, Abramson Family Cancer Research Institute, University of Pennsylvania, 421 Curie Boulevard, 642 BRB II/III, Philadelphia, PA 19104 USA.
  3. Present Address: Institute for Cell Engineering, The Johns Hopkins School of Medicine, 733 North Broadway, Baltimore, MD 21210 USA.

PMID: 29057315 PMCID: PMC5645400 DOI: 10.1038/s41531-017-0032-2

Abstract

The NLRP3 inflammasome signaling pathway is a major contributor to the neuroinflammatory process in the central nervous system. Oxidative stress and mitochondrial dysfunction are key pathophysiological processes of many chronic neurodegenerative diseases, including Parkinson's disease (PD). However, the inter-relationship between mitochondrial defects and neuroinflammation is not well understood. In the present study, we show that impaired mitochondrial function can augment the NLRP3 inflammasome-driven proinflammatory cascade in microglia. Primary mouse microglia treated with the common inflammogen LPS increased NLRP3 and pro-IL-1β expression. Interestingly, exposure of LPS-primed microglial cells to the mitochondrial complex-I inhibitory pesticides rotenone and tebufenpyrad specifically potentiated the NLRP3 induction, ASC speck formation and pro-IL-1β processing to IL-1β in a dose-dependent manner, indicating that mitochondrial impairment heightened the NLRP3 inflammasome-mediated proinflammatory response in microglia. The neurotoxic pesticide-induced NLRP3 inflammasome activation was accompanied by bioenergetic defects and lysosomal dysfunction in microglia. Furthermore, the pesticides enhanced mitochondrial ROS generation in primary microglia, while amelioration of mitochondria-derived ROS by the mitochondria-targeted antioxidant mito-apocynin completely abolished IL-1β release, indicating mitochondrial ROS drives potentiation of the NLRP3 inflammasome in microglia. Exposure to conditioned media obtained from mitochondrial inhibitor-treated, LPS-primed microglial cells, but not unprimed cells, induced dopaminergic neurodegeneration in cultured primary mesencephalic and human dopaminergic neuronal cells (LUHMES). Notably, our in vivo results with chronic rotenone rodent models of PD further support the activation of proinflammatory NLRP3 inflammasome signaling due to mitochondrial dysfunction. Collectively, our results demonstrate that mitochondrial impairment in microglia can amplify NLRP3 inflammasome signaling, which augments the dopaminergic neurodegenerative process.

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