The pore-forming subunit Kir6.1 of the K-ATP channel negatively regulates the NLRP3 inflammasome to control insulin resistance by interacting with NLRP3

Ren-Hong Du,Ming Lu,Gang Hu,Jian-Hua Ding,Guangyu Wu,Cong Wang

doi:10.1038/s12276-019-0291-6

Abstract

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.

Highlights

Insulin resistance is a pathological complication and a hallmark of type 2 diabetes (T2D), characterized by an unresponsiveness of cells in the primary metabolic tissues to the hormone insulin[1]
As an initial approach to directly investigate the role of Kir6.1 in the activation of the NLRP3 inflammasome, we used Kir6.1 KO mice to determine the effect of Kir6.1 depletion on the expression of caspase-1 and IL-1β
Among several proinflammatory cytokines studied, including IL-1β, IL-6, tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ), IL-1β was the only cytokine found to be present at significantly higher levels in the serum of Kir6.1 KO mice than in WT mice (Fig. 1c)

Summary

Introduction

Insulin resistance is a pathological complication and a hallmark of type 2 diabetes (T2D), characterized by an unresponsiveness of cells in the primary metabolic tissues (including liver, skeletal muscle, and adipose tissues) to the hormone insulin[1]. Inflammation accompanying excessive activation of inflammasomes, the nucleotide-binding, oligomerization domain (NOD)-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome, represents a key component contributing to insulin resistance and has been implicated in the development of metabolic diseases, including T2D2–6. Inflammasomes are large intracellular multiprotein complexes that play a crucial role in host defense, against a variety of pathogens[7,8]. The NLRP3 inflammasome consists of three subunits, the scaffold NLRP3, the adaptor apoptotic speck protein, which contains a caspase recruitment domain (ASC) and the downstream effector procaspase-1, which can assemble in response to stimulation by pathogens and danger signals. A two-signal model has been proposed for the activation of the NLRP3 inflammasome, in which signal 1 or the priming signal is provided by microbial or endogenous molecules that activate the transcription factor NF-κB to induce the expression of NLRP3 and pro-

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Conclusion