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

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.

SUBMITTER: Du RH

PROVIDER: S-EPMC6802643 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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

Du Ren-Hong RH Lu Ming M Wang Cong C Ding Jian-Hua JH Wu Guangyu G Hu Gang G

Experimental & molecular medicine 20190806 8

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<sup>+</sup> 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 inflamm ...[more]

PMID: 31387986

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Project description:Inflammation is induced because of interplay among multiple signaling pathways and molecules during infectious and noninfectious tissue injuries. Crosstalk between Toll-like receptor-4 signaling and the neuronal apoptosis inhibitor protein, major histocompatibility class 2 transcription activator, incompatibility locus protein from Podospora anserina, and telomerase-associated protein (NACHT), leucine-rich repeat (LRR), and pyrin domain-containing protein 3 (NLRP3) inflammasome against pathogen- or damage-associated molecular patterns can cause exaggerated inflammation. We previously established that the Toll-like receptor-4-interacting SPA4 peptide suppresses gram-negative bacterial lipopolysaccharide (Toll-like receptor-4 ligand)-induced nuclear factor-κB and inflammatory response. In the present study, we hypothesized that the SPA4 peptide exerts its anti-inflammatory effects by suppressing the crosstalk between Toll-like receptor-4 signaling and the NLRP3 inflammasome. We evaluated binding of the lipopolysaccharide-ligand to cell-surface Toll-like receptor-4 in the presence or absence of adenosine triphosphate (an NLRP3 inflammasome inducer) by flow cytometry. The expression and activity of NLRP3 inflammasome-related parameters were studied in cells challenged with lipopolysaccharide and adenosine triphosphate using molecular and immunologic methods. The cells were challenged with lipopolysaccharide and treated with SPA4 peptide before (pre-adenosine triphosphate) or after (post-adenosine triphosphate) secondary challenge with adenosine triphosphate. Our data demonstrate that the Toll-like receptor-4-interacting SPA4 peptide does not affect the binding of lipopolysaccharide to Toll-like receptor-4 in the presence or absence of adenosine triphosphate. We also found that the SPA4 peptide inhibits mRNA and cellular protein levels of pro-interleukin-1β and NLRP3, formation of the NLRP3 inflammasome, caspase activity, and release of interleukin-1β. Furthermore, the SPA4 peptide treatment reduced the secreted levels of interleukin-1β from cells overexpressing Toll-like receptor-4 compared with cells expressing the dominant-negative form of Toll-like receptor-4. Together our results suggest that the SPA4 peptide exerts its anti-inflammatory activity by suppressing Toll-like receptor-4-priming of the NLRP3 inflammasome.

Dataset Information

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

Publications

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

Similar Datasets

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