Premium
MITO‐APOCYNIN, A NOVEL MITOCHONDRIA‐TARGETED DERIVATIVE OF APOCYNIN, INHIBITS NLRP3 INFLAMMASOME ACTIVATION IN PRIMARY MURINE MICROGLIA IN DOPAMINERGIC NEUROTOXIC MODELS
Author(s) -
Sarkar Souvarish,
Panicker Nikhil,
Neal Matthew Layne,
Harischandra Dilshan,
Jin Huajun,
anantharam Vellareddy,
Kalyanaraman Balaraman,
Kanthasamy Arthi,
Kanthasamy Anumantha
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1195.2
Subject(s) - apocynin , inflammasome , microglia , rotenone , neuroinflammation , mitochondrion , mitochondrial ros , neurotoxicity , chemistry , nadph oxidase , microbiology and biotechnology , reactive oxygen species , pharmacology , superoxide , inflammation , biology , biochemistry , immunology , enzyme , organic chemistry , toxicity
The NLRP3 inflammasome signaling pathway has recently been recognized as a major player in neuro‐inflammation in the CNS. Oxidative stress and mitochondrial dysfunction are known to play key roles in the pathophysiological processes of many neurodegenerative diseases, including Parkinson's disease (PD). To date, the relationship between mitochondrial defects and neuro‐inflammation is not well understood. In the present study, we show that neurotoxic pesticide‐induced mitochondrial impairment induces the NLRP3 inflammasome's pro‐inflammatory cascade in primary microglia. Treating primary mouse microglia with LPS induced NLRP3 and pro‐IL1β expression. Interestingly, exposing LPS‐primed microglial cells to the mitochondrial complex I inhibitory pesticides rotenone and tebufenpyrad potentiated activation of the NLRP3 inflammasome and processing of pro‐IL‐1β in a time‐ and dose‐dependent manner, indicating that mitochondrial impairment heightened the pro‐inflammatory response in microglia. Morphological analysis revealed that rotenone and tebufenpyrad significantly increased mitochondrial circularity and solidity in LPS‐primed microglia as well as decreased mitochondrial perimeter relative to unprimed microglia, thereby augmenting mitochondrial fragmentation during neurotoxic pesticide‐induced inflammasome activation. Immunocytochemistry (ICC) revealed enhanced mitochondrial superoxide production in rotenone‐ and tebufenpyrad‐treated LPS‐primed microglia via the co‐localization of NLRP3 and mitochondrial superoxide in these cells. Finally, mito‐apocynin, a novel mitochondria‐targeted derivative of apocynin, was able to significantly reduce neurotoxic pesticide‐induced NLRP3 inflammasome activation through attenuation of mitochondrial superoxide generation from damaged mitochondria. Collectively, our studies demonstrate for the first time that mitochondrial impairment resulting from neurotoxic pesticide exposure can activate NLRP3 inflammasome signaling in microglia, further augmenting pro‐inflammatory events in the brain. Also, for the first time, we show that reducing mitochondrial superoxide generation by mitochondria‐targeted pharmacological agents can attenuate the inflammasome activation. Support or Funding Information Supported by NS088206 and ES19267