Inhibition of NADPH Oxidase (NOX) 2 Mitigates Colitis in Mice with Impaired Macrophage AMPK Function

被引:11
作者
Banskota, Suhrid [1 ,2 ]
Wang, Huaqing [1 ,2 ]
Kwon, Yun Han [1 ,2 ]
Gautam, Jaya [3 ,4 ,5 ]
Haq, Sabah [1 ,2 ]
Grondin, Jensine [1 ,2 ]
Steinberg, Gregory R. [3 ,4 ,5 ]
Khan, Waliul I. [1 ,2 ,3 ]
机构
[1] McMaster Univ, Farncombe Family Digest Hlth Res Inst, Hamilton, ON L8S 4L8, Canada
[2] McMaster Univ, Dept Pathol & Mol Med, Hamilton, ON L8S 4L8, Canada
[3] McMaster Univ, Ctr Metab Obes & Diabet Res, Hamilton, ON L8S 4L8, Canada
[4] McMaster Univ, Dept Med, Hamilton, ON L8S 4L8, Canada
[5] McMaster Univ, Dept Biochem & Biomed Sci, Hamilton, ON L8S 4L8, Canada
基金
加拿大健康研究院;
关键词
macrophages; AMPK; NOX2; inflammation; autophagy; colitis; INNATE IMMUNE-RESPONSES; ACTIVATION; SUSCEPTIBILITY; INFLAMMATION; EXPRESSION; DISEASE;
D O I
10.3390/biomedicines11051443
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Macrophage adenosine monophosphate-activated protein kinase (AMPK) limits the development of experimental colitis. AMPK activation inhibits NADPH oxidase (NOX) 2 expression, reactive oxygen species (ROS) generation, and pro-inflammatory cytokine secretion in macrophages during inflammation, while increased NOX2 expression is reported in experimental models of colitis and inflammatory bowel disease (IBD) patients. Although there are reductions in AMPK activity in IBD, it remains unclear whether targeted inhibition of NOX2 in the presence of defective AMPK can reduce the severity of colitis. Here, we investigate whether the inhibition of NOX2 ameliorates colitis in mice independent of AMPK activation. Our study identified that VAS2870 (a pan-Nox inhibitor) alleviated dextran sodium sulfate (DSS)-induced colitis in macrophage-specific AMPKfi1-deficient (AMPK beta 1(LysM)) mice. Additionally, VAS2870 blocked LPS-induced TLR-4 and NOX2 expression, ROS production, nuclear translocation of NF-kappa B, and pro-inflammatory cytokine secretion in bone marrow-derived macrophages (BMDMs) from AMPK beta 1(LysM) mice, whereas sodium salicylate (SS; AMPK fi1 activator) did not. Both VAS2870 and SS inhibited LPS-induced NOX2 expression, ROS production, and pro-inflammatory cytokine secretions in bone marrow-derived macrophages (BMDMs) from wildtype (AMPK beta 1(fl/fl)) mice but only VAS2870 inhibited these effects of LPSs in AMPK beta 1(LysM) BMDMs. Furthermore, in macrophage cells (RAW264.7), both SS and VAS2870 inhibited ROS production and the secretion of pro-inflammatory cytokines and reversed the impaired autophagy induced by LPSs. These data suggest that inhibiting NOX2 can reduce inflammation independent of AMPK in colitis.
引用
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页数:13
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