Excessive and dysregulated inflammation is known to contribute to disease progression. HSP90 is an intracellular chaperone known to regulate inflammatory processes including the NLRP3 inflammasome and secretion of the pro‐inflammatory cytokine interleukin(IL)‐1β. Here, primarily using an in vitro inflammasome ASC speck assay, and an in vivo model of murine peritonitis, we tested the utility of HSP90 inhibitors as anti‐inflammatory molecules. We report that the HSP90 inhibitor EC144 effectively inhibited inflammatory processes including priming and activation of NLRP3 in vitro and in vivo. A specific inhibitor of the β HSP90 isoform was ineffective suggesting the importance of the α isoform in inflammatory signalling. EC144 inhibited IL‐1β and IL‐6 in vivo when administered orally, and was brain‐penetrant. These data suggest that HSP90 inhibitors may be useful for targeting inflammation in diverse diseases that are worsened by the presence of inflammation.

中文翻译：

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HSP90 抑制剂对 NLRP3 炎性体的抑制作用。

已知过度和失调的炎症会导致疾病进展。HSP90 是一种细胞内分子伴侣，已知可调节炎症过程，包括 NLRP3 炎性体和促炎细胞因子白细胞介素 (IL)-1β 的分泌。在这里，我们主要使用体外炎症小体 ASC 斑点试验和小鼠腹膜炎的体内模型，测试了 HSP90 抑制剂作为抗炎分子的效用。我们报告 HSP90 抑制剂 EC144在体外和体内有效抑制炎症过程，包括引发和激活 NLRP3. β HSP90 同种型的特异性抑制剂无效，表明 α 同种型在炎症信号传导中的重要性。口服时， EC144在体内抑制 IL-1β 和 IL-6 ，并且具有脑渗透性。这些数据表明，HSP90 抑制剂可用于针对因炎症而恶化的多种疾病中的炎症。