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Deubiquitinating enzymes (DUBs): DoUBle-edged swords in CNS autoimmunity.

ABSTRACT: Multiple sclerosis (MS) is the most common autoimmune disease of the CNS. The etiology of MS is still unclear but it is widely recognized that both genetic and environmental factors contribute to its pathogenesis. Immune signaling and responses are critically regulated by ubiquitination, a posttranslational modification that is promoted by ubiquitinating enzymes and inhibited by deubiquitinating enzymes (DUBs). Genome-wide association studies (GWASs) identified that polymorphisms in or in the vicinity of two human DUB genes TNFAIP3 and USP18 were associated with MS susceptibility. Studies with experimental autoimmune encephalomyelitis (EAE), an animal model of MS, have provided biological rationale for the correlation between these DUBs and MS. Additional studies have shown that other DUBs are also involved in EAE by controlling distinct cell populations. Therefore, DUBs are emerging as crucial regulators of MS/EAE and might become potential therapeutic targets for the clinical treatment of MS.

SUBMITTER: Ruan J

PROVIDER: S-EPMC7132956 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Deubiquitinating enzymes (DUBs): DoUBle-edged swords in CNS autoimmunity.

Ruan Jing J Schlüter Dirk D Wang Xu X

Journal of neuroinflammation 20200406 1

Multiple sclerosis (MS) is the most common autoimmune disease of the CNS. The etiology of MS is still unclear but it is widely recognized that both genetic and environmental factors contribute to its pathogenesis. Immune signaling and responses are critically regulated by ubiquitination, a posttranslational modification that is promoted by ubiquitinating enzymes and inhibited by deubiquitinating enzymes (DUBs). Genome-wide association studies (GWASs) identified that polymorphisms in or in the vi ...[more]

PMID: 32248814

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Project description:BackgroundReactive oxygen species (ROS) often promote acute brain injury after stroke, but their roles in the recovery phase have not been well studied. We tested the hypothesis that ROS activity mediated by NADPH oxidase 2 (NOX2) contributes to acute brain injury but promotes functional recovery during the delayed phase, which is linked with neuroinflammation, autophagy, angiogenesis, and the PI3K/Akt signaling pathway.MethodsWe used the NOX2 inhibitor apocynin to study the role of NOX2 in brain injury and functional recovery in a middle cerebral artery occlusion (MCAO) stroke mouse model. Infarct size, neurological deficits and behavior were evaluated on days 3, 7, 10 and 14 after reperfusion. In addition, dynamic NOX2-induced ROS levels were measured by dihydroethidium (DHE) staining. Autophagy, inflammasomes, and angiogenesis were measured by immunofluorescence staining and western blotting. RNA sequencing was performed, and bioinformatics technology was used to analyze differentially expressed genes (DEGs), as well as the enrichment of biological functions and signaling pathways in ischemia penumbra at 7 days after reperfusion. Then, Akt pathway-related proteins were further evaluated by western blotting.ResultsOur results showed that apocynin injection attenuated infarct size and mortality 3 days after stroke but promoted mortality and blocked functional recovery from 5 to 14 days after stroke. DHE staining showed that ROS levels were increased at 3 days after reperfusion and then gradually declined in WT mice, and these levels were significantly reduced by the NOX2 inhibitor apocynin. RNA-Seq analysis indicated that apocynin activated the immune response under hypoxic conditions. The immunofluorescence and western blot results demonstrated that apocynin inhibited the NLRP3 inflammasome and promoted angiogenesis at 3 days but promoted the NLRP3 inflammasome and inhibited angiogenesis at 7 and 14 days after stroke, which was mediated by regulating autophagy activation. Furthermore, RNA-Seq and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated that apocynin injection resulted in PI3K-Akt signaling pathway enrichment after 7 days of MCAO. We then used an animal model to show that apocynin decreased the protein levels of phosphorylated PI3K and Akt and NF-κB p65, confirming that the PI3K-Akt-NF-κB pathway is involved in apocynin-mediated activation of inflammation and inhibition of angiogenesis.ConclusionsNOX2-induced ROS production is a double-edged sword that exacerbates brain injury in the acute phase but promotes functional recovery. This effect appears to be achieved by inhibiting NLRP3 inflammasome activation and promoting angiogenesis via autophagy activation.

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Deubiquitinating enzymes (DUBs): DoUBle-edged swords in CNS autoimmunity.

Publications

Deubiquitinating enzymes (DUBs): DoUBle-edged swords in CNS autoimmunity.

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