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Phagocytosis-related NADPH oxidase 2 subunit gp91phox contributes to neurodegeneration after repeated systemic challenge with lipopolysaccharides

ABSTRACT: Here, we investigated the role of mononuclear phagocytes associated nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX-2) in inflammatory neurodegeneration. Cybb-deficient mice NOX-2 knock-out (KO) and control wild type (WT) mice were treated intraperitoneally daily over four consecutive days with 1 µg/gbw/day LPS. Repeated LPS injections led to inflammation and neuronal loss in the brains of WT mice, which was attenuated after knockout of NOX-2. Transcriptome analysis by RNA-seq of total brain tissue indicated increased LPS-induced upregulation of genes belonging to the reactive oxygen species (ROS) and reactive nitrogen species (RNS) production, complement and lysosome activation as well as apoptosis and necroptosis in WT compared to NOX-2 KO mice.

ORGANISM(S): Mus musculus

PROVIDER: GSE153369 | GEO | 2020/08/03

REPOSITORIES: GEO

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Project description:Reactive nitrogen species (RNS) derived from dietary and salivary inorganic nitrates (NO3-) foment innate host defenses associated with the acidity of the stomach. The mechanisms by which these reactive species exert antibiotic activity in the gastric lumen are, however, poorly understood. To identify targets of RNS, the genetically tractable acid tolerance response (ATR) that enables enteropathogens to survive the harsh acidity of the stomach was screened for signaling pathways responsive to RNS. The nitric oxide (NO) donor spermine NONOate derepressed the Fur regulon that controls secondary lines of resistance against organic acids. Despite inducing a Fur-mediated adaptive response, acidified RNS largely boosted gastric host defenses as demonstrated by the fact that Salmonella bacteria exposed to spermine NONOate during mildly acidic conditions were not only shed in low amounts in feces, but also exhibited ameliorated oral virulence. NO prevented Salmonella from mounting a de novo ATR, but was unable to suppress an already functional protective response, indicating that RNS target regulatory cascades but not the effectors that defend against the rigors of gastric acidity. Transcriptional and translational analyses revealed that the PhoPQ signaling cascade is a critical ATR target of NO in rapidly growing Salmonella. Inhibition of PhoPQ signaling appears to contribute to most of the NO-mediated abrogation of the ATR in log phase bacteria, because the augmented acid sensitivity of phoQ-deficient Salmonella was not further enhanced after RNS treatment. Since PhoPQ-regulated acid resistance is widespread in enteric pathogens, the RNS-mediated inhibition of the Salmonella ATR described herein may represent a common component of the innate host defenses of the gastric lumen. Keywords: acid tolerance response, nitric oxide Microarray analyses were conducted comparing transcript levels of log-phase Salmonella cultured in minimal E salts + 0.4% glucose, pH 4.4 in the presence or absence of 250 ÂµM spermine NONOate for 1 hour. Microarrays were performed in triplicate under identical conditions (3 biological replicates).

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Phagocytosis-related NADPH oxidase 2 subunit gp91phox contributes to neurodegeneration after repeated systemic challenge with lipopolysaccharides

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