INSERM UMR1231, F-21000, Dijon, France.
Université Bourgogne Franche-Comté, F-21000, Dijon, France.
Cell Death Dis. 2019 Mar 15;10(4):256. doi: 10.1038/s41419-019-1491-7.
The NOD-leucine rich repeat and pyrin containing protein 3 (NLRP3) inflammasome is a multi-protein complex, aimed at producing IL-1β in response to danger signals which must be tightly regulated. Here we investigated the importance of the stress sensor, Heat Shock Protein 70 (HSP70) on NLRP3 inflammasome activation. HSP70 deficiency leads to the worsening of NLRP3-dependent peritonitis in mice. HSP70 deficiency also enhances caspase-1 activation and IL-1β production in murine Bone Marrow-Derived Macrophages (BMDMs) under NLRP3 activator treatment in vitro. This observation is associated with an increased number and size of Apoptosis associated Speck-like protein containing a CARD domain (ASC)/NLRP3 specks. Conversely, the overexpression of HSP70 in BMDMs decreases caspase-1 activation and IL-1β production under NLRP3 activator treatment. HSP70 interacts with NLRP3 and this interaction is lost upon NLRP3 inflammasome activation. Heat shock inhibits NLRP3 inflammasome activation in vitro and inhibits peritonitis in mice. Therefore this study provides evidence on the inhibitory role of HSP70 on NLRP3 inflammasome and open the possibility of treating inflammatory diseases via HSP70 induction and/or by hyperthermia.
NOD-亮氨酸丰富重复和富含吡咯的蛋白 3（NLRP3）炎性小体是一种多蛋白复合物，旨在响应危险信号产生 IL-1β，必须对其进行严格调控。在这里，我们研究了应激传感器热休克蛋白 70（HSP70）对 NLRP3 炎性小体激活的重要性。HSP70 缺乏会导致小鼠 NLRP3 依赖性腹膜炎加重。HSP70 缺乏还会增强体外 NLRP3 激活剂处理下的鼠骨髓源性巨噬细胞（BMDM）中 caspase-1 的激活和 IL-1β的产生。这种观察结果与凋亡相关斑点样蛋白（ASC）/NLRP3 斑点的数量和大小增加有关。相反，在 NLRP3 激活剂处理下，BMDM 中 HSP70 的过表达会降低 caspase-1 的激活和 IL-1β的产生。HSP70 与 NLRP3 相互作用，这种相互作用在 NLRP3 炎性小体激活时丢失。热休克可抑制体外 NLRP3 炎性小体的激活，并抑制小鼠腹膜炎。因此，本研究为 HSP70 对 NLRP3 炎性小体的抑制作用提供了证据，并为通过 HSP70 诱导和/或高热治疗炎症性疾病开辟了可能性。
