Shenglong Chen1, Chaogang Tang2, Hongguang Ding1, Zhonghua Wang3, Xinqiang Liu1, Yunfei Chai4, Wenqiang Jiang1, Yongli Han1, Hongke Zeng1. 1. Department of Critical Care Medicine, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China. 2. Department of Cerebrovascular Disease, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, China. 3. Department of Gerontological Critical Care Medicine, Guangdong Provincial People's Hospital/Guangdong Academy of Medical Sciences/Guangdong Provincial Geriatrics Institute, Guangzhou, China. 4. Anesthesiology Department of Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
Abstract
Background: The NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome has been identified as an important mediator of blood-brain-barrier disruption in sepsis-associated encephalopathy (SAE). However, no information is available concerning the critical upstream regulators of SAE. Methods: Lipopolysaccharide (LPS) was used to establish an in vitro model of blood-brain barrier (BBB) disruption and an in vivo model of SAE. Disruption of BBB integrity was assessed by measuring the expression levels of tight-junction proteins. NLRP3 inflammasome activation, pro-inflammatory cytokines levels, and neuroapoptosis were measured using biochemical assays. Finally, the FITC-dextran Transwell assay and Evan's blue dye assay were used to assess the effect of Maf1 on LPS-induced endothelial permeability in vitro and in vivo. Results: We found that Maf1 significantly suppressed the brain inflammatory response and neuroapoptosis induced by LPS in vivo and in vitro. Notably, Maf1 downregulated activation of the NF-κB/p65-induced NLRP3 inflammasome and the expression of pro-inflammatory cytokines. In addition, we found that Maf1 and p65 directly bound to the NLRP3 gene promoter region and competitively regulated the function of NLRP3 in inflammations. Moreover, overexpression of NLRP3 reversed the effects of p65 on BBB integrity, apoptosis, and inflammation in response to LPS. Our study revealed novel role for Maf1 in regulating NF-κB-mediated inflammasome formation, which plays a prominent role in SAE. Conclusions: Regulation of Maf1 might be a therapeutic strategy for SAE and other neurodegenerative diseases associated with inflammation.
Background: The NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome has been identified as an important mediator of blood-brain-barrier disruption in sepsis-associated encephalopathy (SAE). However, no information is available concerning the critical upstream regulators of SAE. Methods:Lipopolysaccharide (LPS) was used to establish an in vitro model of blood-brain barrier (BBB) disruption and an in vivo model of SAE. Disruption of BBB integrity was assessed by measuring the expression levels of tight-junction proteins. NLRP3 inflammasome activation, pro-inflammatory cytokines levels, and neuroapoptosis were measured using biochemical assays. Finally, the FITC-dextran Transwell assay and Evan's blue dye assay were used to assess the effect of Maf1 on LPS-induced endothelial permeability in vitro and in vivo. Results: We found that Maf1 significantly suppressed the brain inflammatory response and neuroapoptosis induced by LPS in vivo and in vitro. Notably, Maf1 downregulated activation of the NF-κB/p65-induced NLRP3 inflammasome and the expression of pro-inflammatory cytokines. In addition, we found that Maf1 and p65 directly bound to the NLRP3 gene promoter region and competitively regulated the function of NLRP3 in inflammations. Moreover, overexpression of NLRP3 reversed the effects of p65 on BBB integrity, apoptosis, and inflammation in response to LPS. Our study revealed novel role for Maf1 in regulating NF-κB-mediated inflammasome formation, which plays a prominent role in SAE. Conclusions: Regulation of Maf1 might be a therapeutic strategy for SAE and other neurodegenerative diseases associated with inflammation.
Authors: N Joan Abbott; Adjanie A K Patabendige; Diana E M Dolman; Siti R Yusof; David J Begley Journal: Neurobiol Dis Date: 2009-08-05 Impact factor: 5.996
Authors: Auvro R Mridha; Alexander Wree; Avril A B Robertson; Matthew M Yeh; Casey D Johnson; Derrick M Van Rooyen; Fahrettin Haczeyni; Narci C-H Teoh; Christopher Savard; George N Ioannou; Seth L Masters; Kate Schroder; Matthew A Cooper; Ariel E Feldstein; Geoffrey C Farrell Journal: J Hepatol Date: 2017-02-03 Impact factor: 25.083