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Carnosol inhibits inflammasome activation by directly targeting HSP90 to treat inflammasome-mediated diseases.
Cell Death & Disease ( IF 8.1 ) Pub Date : 2020-04-20 , DOI: 10.1038/s41419-020-2460-x Wei Shi 1, 2 , Guang Xu 1 , Xiaoyan Zhan 3 , Yuan Gao 1, 4 , Zhilei Wang 1, 5 , Shubin Fu 1 , Nan Qin 1 , Xiaorong Hou 1 , Yongqiang Ai 1, 2 , Chunyu Wang 1 , Tingting He 3 , Hongbin Liu 1 , Yuanyuan Chen 1 , Yan Liu 1 , Jiabo Wang 1 , Ming Niu 1 , Yuming Guo 3 , Xiaohe Xiao 3 , Zhaofang Bai 1
Cell Death & Disease ( IF 8.1 ) Pub Date : 2020-04-20 , DOI: 10.1038/s41419-020-2460-x Wei Shi 1, 2 , Guang Xu 1 , Xiaoyan Zhan 3 , Yuan Gao 1, 4 , Zhilei Wang 1, 5 , Shubin Fu 1 , Nan Qin 1 , Xiaorong Hou 1 , Yongqiang Ai 1, 2 , Chunyu Wang 1 , Tingting He 3 , Hongbin Liu 1 , Yuanyuan Chen 1 , Yan Liu 1 , Jiabo Wang 1 , Ming Niu 1 , Yuming Guo 3 , Xiaohe Xiao 3 , Zhaofang Bai 1
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Aberrant activation of inflammasomes, a group of protein complexes, is pathogenic in a variety of metabolic and inflammation-related diseases. Here, we report that carnosol inhibits NLRP3 inflammasome activation by directly targeting heat-shock protein 90 (HSP90), which is essential for NLRP3 inflammasome activity, thereby treating inflammasome-mediated diseases. Our data demonstrate that carnosol inhibits NLRP3 inflammasome activation in primary mouse bone marrow-derived macrophages (BMDMs), THP-1 cells and human peripheral blood mononuclear cells (hPBMCs). Mechanistically, carnosol inhibits inflammasome activation by binding to HSP90 and then inhibiting its ATPase activity. In vivo, our results show that carnosol has remarkable therapeutic effects in mouse models of NLRP3 inflammasome-mediated diseases, including endotoxemia and nonalcoholic steatohepatitis (NASH). Our data also suggest that intraperitoneal administration of carnosol (120 mg/kg) once daily for two weeks is well tolerated in mice. Thus, our study reveals the inhibitory effect of carnosol on inflammasome activation and demonstrates that carnosol is a safe and effective candidate for the treatment of inflammasome-mediated diseases.
中文翻译：
鼠尾草酚通过直接靶向HSP90来治疗炎性体介导的疾病，从而抑制了炎性体的活化。
炎性小体（一组蛋白质复合物）的异常激活是多种代谢和炎症相关疾病的致病原。在这里，我们报道鼠尾草酚通过直接靶向热休克蛋白90（HSP90）来抑制NLRP3炎性体的激活，而热休克蛋白90对NLRP3炎性体的活性至关重要，从而治疗了炎性体介导的疾病。我们的数据表明，鼠尾草酚能抑制原代小鼠骨髓源性巨噬细胞（BMDM），THP-1细胞和人外周血单核细胞（hPBMC）中的NLRP3炎性体活化。从机理上讲，鼠尾草酚通过与HSP90结合然后抑制其ATPase活性来抑制炎性体的活化。在体内，我们的结果表明，鼠尾草酚对NLRP3炎症小体介导的疾病的小鼠模型具有显着的治疗作用，包括内毒素血症和非酒精性脂肪性肝炎（NASH）。我们的数据还表明，在小鼠中每天两次腹膜内给予鼠尾草酚（120 mg / kg）的耐受性良好。因此，我们的研究揭示了鼠尾草酚对炎性体激活的抑制作用，并证明鼠尾草酚是治疗炎性体介导的疾病的安全有效候选者。
更新日期：2020-04-24
中文翻译：
鼠尾草酚通过直接靶向HSP90来治疗炎性体介导的疾病，从而抑制了炎性体的活化。
炎性小体（一组蛋白质复合物）的异常激活是多种代谢和炎症相关疾病的致病原。在这里，我们报道鼠尾草酚通过直接靶向热休克蛋白90（HSP90）来抑制NLRP3炎性体的激活，而热休克蛋白90对NLRP3炎性体的活性至关重要，从而治疗了炎性体介导的疾病。我们的数据表明，鼠尾草酚能抑制原代小鼠骨髓源性巨噬细胞（BMDM），THP-1细胞和人外周血单核细胞（hPBMC）中的NLRP3炎性体活化。从机理上讲，鼠尾草酚通过与HSP90结合然后抑制其ATPase活性来抑制炎性体的活化。在体内，我们的结果表明，鼠尾草酚对NLRP3炎症小体介导的疾病的小鼠模型具有显着的治疗作用，包括内毒素血症和非酒精性脂肪性肝炎（NASH）。我们的数据还表明，在小鼠中每天两次腹膜内给予鼠尾草酚（120 mg / kg）的耐受性良好。因此，我们的研究揭示了鼠尾草酚对炎性体激活的抑制作用，并证明鼠尾草酚是治疗炎性体介导的疾病的安全有效候选者。
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