Maf1 Ameliorates Sepsis-Associated Encephalopathy by Suppressing the NF-kB/NLRP3 Inflammasome Signaling Pathway.
Maf1 Ameliorates Sepsis-Associated Encephalopathy by Suppressing the NF-kB/NLRP3 Inflammasome Signaling Pathway.
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Maf1通过抑制NF-kB/NLRP3炎性小体信号通路改善败血症相关脑病
DOI：
10.3389/fimmu.2020.594071
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发表时间：
2020
影响因子：
7.3
通讯作者：
Zeng H
中科院分区：
文献类型：
--
作者：
Chen S;Tang C;Ding H;Wang Z;Liu X;Chai Y;Jiang W;Han Y;Zeng H
含 NOD、LRR 和 Pyrin 结构域的蛋白 3 (NLRP3) 炎症小体已被确定为脓毒症相关脑病 (SAE) 血脑屏障破坏的重要介质。然而，没有关于 SAE 关键上游监管机构的信息。使用脂多糖（LPS）建立血脑屏障（BBB）破坏的体外模型和SAE的体内模型。通过测量紧密连接蛋白的表达水平来评估血脑屏障完整性的破坏。使用生化测定测量 NLRP3 炎性体激活、促炎细胞因子水平和神经细胞凋亡。最后，使用 FITC-葡聚糖 Transwell 测定和埃文蓝染料测定来评估 Maf1 对体外和体内 LPS 诱导的内皮通透性的影响。 我们发现Maf1在体内和体外均显着抑制LPS诱导的脑炎症反应和神经细胞凋亡。值得注意的是，Maf1 下调 NF-κB/p65 诱导的 NLRP3 炎症小体的激活和促炎细胞因子的表达。此外，我们发现Maf1和p65直接结合NLRP3基因启动子区域并竞争性调节NLRP3在炎症中的功能。此外，NLRP3 的过度表达逆转了 p65 对 BBB 完整性、细胞凋亡和 LPS 反应炎症的影响。我们的研究揭示了 Maf1 在调节 NF-κB 介导的炎症小体形成中的新作用，这在 SAE 中发挥着重要作用。 Maf1 的调节可能是 SAE 和其他与炎症相关的神经退行性疾病的治疗策略。
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. 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. 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. Regulation of Maf1 might be a therapeutic strategy for SAE and other neurodegenerative diseases associated with inflammation.
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影响因子：
4.6
作者：
Chen X;Wang N;Zhu Y;Lu Y;Liu X;Zheng J
通讯作者：
Zheng J
影响因子：
15.1
作者：
Erickson, Michelle A.;Banks, William A.
通讯作者：
Banks, William A.
影响因子：
15.1
作者：
Kohman, Rachel A.;Rhodes, Justin S.
通讯作者：
Rhodes, Justin S.
DOI：
10.1016/j.bbrc.2015.02.029
发表时间：
2015-03-13
影响因子：
3.1
作者：
Boaru, Sorina Georgiana;Borkham-Kamphorst, Erawan;Weiskirchen, Ralf
通讯作者：
Weiskirchen, Ralf
影响因子：
5.1
作者：
Fann, David Yang-Wei;Lim, Yun-An;Arumugam, Thiruma V.
通讯作者：
Arumugam, Thiruma V.