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Mol Immunol ; 105: 76-85, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30496979

RESUMO

Activation of NLRP3 inflammasomes is crucial in the pathological process of Ulcerative colitis (UC), which could be negatively regulated by PINK1/Parkin-driven mitophagy. Palmatine is a herb derived isoquinoline alkaloid with potent anti-inflammatory and anti-bacteria activities. In present study, we evaluated the effect of palmatine on dextran sulfate sodium (DSS)-induced mice colitis and examined whether its effect is exerted by promoting mitophagy-mediated NLRP3 inflammasome inactivation. The result showed that palmatine (40, 100 mg/kg) significantly prevented bodyweight loss and colonic shortening in DSS mice, and reduced the disease activity index and histopathologic score. The levels of MPO, IL-1ß, TNF-α and the number of F4/80+ cells in colon of DSS mice were remarkably decreased by palmatine. Moreover, palmatine suppressed NLRP3 inflammasomes activation, but enhanced the expression of the mitophagy-related proteins involving LC3, PINK1 and Parkin in colonic tissue of DSS mice. These effects was consistent with the in vitro data revealing that palmatine inhibited the activation of NLRP3 inflammasomes, while promoted the expression and mitochondrial recruitment of PINK1 and Parkin in THP-1 cell differentiated macrophages. Furthermore, the effect of palmatine on THP-1 cells was neutralized by a mitophagy inhibitor Cyclosporin A (CsA) and PINK1-siRNA. In parallel, CsA significantly attenuated the therapeutic effect of palmatine in DSS mice, illustrating that the anti-colitis effect of palmatine is closely related to mitophagy. Taken together, the current results demonstrated that palmatine protected mice against DSS-induced colitis by facilitating PINK1/Parkin-driven mitophagy and thus inactivating NLRP3 inflammasomes in macrophage.


Assuntos
Colite , Sulfato de Dextrana/toxicidade , Inflamassomos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Ácido Palmítico/farmacologia , Animais , Colite/induzido quimicamente , Colite/imunologia , Colite/patologia , Colite/prevenção & controle , Ciclosporina/farmacologia , Modelos Animais de Doenças , Humanos , Masculino , Camundongos Endogâmicos BALB C , Proteínas Quinases/imunologia , Células THP-1 , Ubiquitina-Proteína Ligases/imunologia
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