Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, Jiangsu, P. R. China.
Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, 1459 Laney Walker Blvd., Augusta, 30912, Georgia, USA.
Exp Mol Med. 2019 Aug 6;51(8):1-13. doi: 10.1038/s12276-019-0291-6.
Excessive activation of the NLRP3 inflammasome is a key component contributing to the pathogenesis of various inflammatory diseases. However, the molecular mechanisms underlying its activation and regulation remain poorly defined. The objective of this study was to explore the possible function of the K channel pore-forming subunit Kir6.1 in regulating NLRP3 inflammasome activation and insulin resistance. Here, we demonstrate that Kir6.1 depletion markedly activates the NLRP3 inflammasome, whereas enhanced Kir6.1 expression produces opposing effects both in mice in vivo and in primary cells in vitro. We also demonstrate that Kir6.1 controls insulin resistance by inhibiting NLRP3 inflammasome activation in mice. We further show that Kir6.1 physically associates with NLRP3 and thus inhibits the interactions between the NLRP3 inflammasome subunits. Our results reveal a previously unrecognized function of Kir6.1 as a negative regulator of the NLRP3 inflammasome and insulin resistance, which is mediated by virtue of its ability to inhibit NLRP3 inflammasome assembly. These data provide novel insights into the regulatory mechanism of NLRP3 inflammasome activation and suggest that Kir6.1 is a promising therapeutic target for inflammasome-mediated inflammatory diseases.
NLRP3 炎性小体的过度激活是导致各种炎症性疾病发病机制的关键组成部分。然而，其激活和调节的分子机制仍未完全明确。本研究旨在探讨 K 通道孔形成亚基 Kir6.1 在调节 NLRP3 炎性小体激活和胰岛素抵抗中的可能作用。在这里，我们证明 Kir6.1 耗竭可显著激活 NLRP3 炎性小体，而增强的 Kir6.1 表达在体内的小鼠和体外的原代细胞中均产生相反的作用。我们还证明 Kir6.1 通过抑制 NLRP3 炎性小体激活来控制小鼠的胰岛素抵抗。我们进一步表明，Kir6.1 与 NLRP3 物理结合，从而抑制 NLRP3 炎性小体亚基之间的相互作用。我们的结果揭示了 Kir6.1 作为 NLRP3 炎性小体和胰岛素抵抗的负调节剂的先前未被认识的功能，这是通过其抑制 NLRP3 炎性小体组装的能力介导的。这些数据为 NLRP3 炎性小体激活的调节机制提供了新的见解，并表明 Kir6.1 是一种有希望的治疗炎性小体介导的炎症性疾病的靶点。
