Posttreatment of Maresin1 Inhibits NLRP3 inflammasome activation via promotion of NLRP3 ubiquitination
Posttreatment of Maresin1 Inhibits NLRP3 inflammasome activation via promotion of NLRP3 ubiquitination
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DOI：
10.1096/fj.202000665rr
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发表时间：
2020-07
期刊：
影响因子：
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通讯作者：
Sisi Zheng;Min-qi Ma;Zhongwang Li;Y. Hao;Hui Li;Pan-Han Fu;S. Jin
中科院分区：
文献类型：
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作者：
Sisi Zheng;Min-qi Ma;Zhongwang Li;Y. Hao;Hui Li;Pan-Han Fu;S. Jin
Maresin1是一种有效的脂质介质，在多种炎症性疾病中显示出潜在的抗炎活性，然而，其潜在的机制仍不清楚。NLRP3炎症体过度激活已在多种炎症性疾病中建立。在这里，我们发现maresin1剂量依赖地抑制NLRP3炎症体的激活以及随后的caspase-1激活和IL-1β的分泌。这种抑制作用可被cAMP-PKA信号通路的抑制剂Kh7和H89逆转。由maresin1诱导的PKA激酶活化导致巨噬细胞中K63连接的NLRP3泛素化。在脂多糖诱导的脓毒症小鼠模型中，Maresin1通过抑制NLRP3体内炎症小体来减少血清IL-1β的分泌。Maresin1也能抑制MSU诱导的腹膜炎。本研究提示，maresin1是NLRP3炎症性小体激活的抑制剂，可用于临床治疗NLRP3炎症性疾病。
Maresin1 is a potent lipid mediator exhibiting potential anti‐inflammatory activity in a variety of inflammatory diseases, however, the underlying mechanisms remain poorly understood. Excessive activation of NLRP3 inflammasome has been established in multiple inflammatory diseases. Here, we show that Maresin1 dose‐dependently inhibited the NLRP3 inflammasome activation and subsequent caspase‐1 activation and IL‐1β secretion. This inhibitory effect could be reversed by KH7 and H89, the inhibitors of the cAMP‐PKA signaling pathway. Activation of PKA kinase induced by Maresin1 led to the K63‐linked ubiquitination of NLRP3 in macrophages. Maresin1 attenuated serum IL‐1β secretion through inhibition of NLRP3 inflammasome in vivo using Nlrp3‐deficient mouse models of lipopolysaccharide (LPS)‐induced sepsis. Maresin1 also repressed MSU‐induced peritonitis. This study suggests that Maresin1 is an inhibitor of NLRP3 inflammasome activation and can be used clinically in the treatment of NLRP3 inflammasome‐driven inflammatory diseases.