TWIK2 钾离子外流通道在巨噬细胞中介导 NLRP3 炎性小体诱导的炎症反应。
The TWIK2 Potassium Efflux Channel in Macrophages Mediates NLRP3 Inflammasome-Induced Inflammation.
机构信息
Department of Pharmacology and the Center for Lung and Vascular Biology, The University of Illinois College of Medicine, Chicago, IL 60612, USA.
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
出版信息
Immunity. 2018 Jul 17;49(1):56-65.e4. doi: 10.1016/j.immuni.2018.04.032. Epub 2018 Jun 26.
Abstract
Potassium (K) efflux across the plasma membrane is thought to be an essential mechanism for ATP-induced NLRP3 inflammasome activation, yet the identity of the efflux channel has remained elusive. Here we identified the two-pore domain K channel (K) TWIK2 as the K efflux channel triggering NLRP3 inflammasome activation. Deletion of Kcnk6 (encoding TWIK2) prevented NLRP3 activation in macrophages and suppressed sepsis-induced lung inflammation. Adoptive transfer of Kcnk6 macrophages into mouse airways after macrophage depletion also prevented inflammatory lung injury. The K efflux channel TWIK2 in macrophages has a fundamental role in activating the NLRP3 inflammasome and consequently mediates inflammation, pointing to TWIK2 as a potential target for anti-inflammatory therapies.
摘要
钾（K）跨质膜外流被认为是 ATP 诱导 NLRP3 炎性体激活的一个必要机制，但外流通道的身份仍然难以捉摸。在这里，我们鉴定出双孔域钾通道（K）TWIK2 是触发 NLRP3 炎性体激活的 K 外流通道。Kcnk6（编码 TWIK2）的缺失阻止了巨噬细胞中 NLRP3 的激活，并抑制了脓毒症引起的肺部炎症。巨噬细胞耗竭后，将 Kcnk6 巨噬细胞过继转移到小鼠气道中也可防止炎症性肺损伤。巨噬细胞中的 K 外流通道 TWIK2 在激活 NLRP3 炎性体方面起着基础性作用，从而介导炎症，表明 TWIK2 是抗炎治疗的潜在靶点。
相似文献
1
The TWIK2 Potassium Efflux Channel in Macrophages Mediates NLRP3 Inflammasome-Induced Inflammation.
Immunity. 2018 Jul 17;49(1):56-65.e4. doi: 10.1016/j.immuni.2018.04.032. Epub 2018 Jun 26.
2
Endosomal trafficking of two-pore K efflux channel TWIK2 to plasmalemma mediates NLRP3 inflammasome activation and inflammatory injury.
Elife. 2023 May 9;12:e83842. doi: 10.7554/eLife.83842.
3
Extracellular histones promote TWIK2-dependent potassium efflux and associated NLRP3 activation in alveolar macrophages during sepsis-induced lung injury.
Inflamm Res. 2024 Jul;73(7):1137-1155. doi: 10.1007/s00011-024-01888-3. Epub 2024 May 11.
4
ML365 inhibits TWIK2 channel to block ATP-induced NLRP3 inflammasome.
Acta Pharmacol Sin. 2022 Apr;43(4):992-1000. doi: 10.1038/s41401-021-00739-9. Epub 2021 Aug 2.
5
Inhibition of sphingosine-1-phosphate receptor 3 suppresses ATP-induced NLRP3 inflammasome activation in macrophages TWIK2-mediated potassium efflux.
Front Immunol. 2023 Jan 31;14:1090202. doi: 10.3389/fimmu.2023.1090202. eCollection 2023.
6
Two-pore potassium channel TREK-1 (K2P2.1) regulates NLRP3 inflammasome activity in macrophages.
Am J Physiol Lung Cell Mol Physiol. 2024 Mar 1;326(3):L367-L376. doi: 10.1152/ajplung.00313.2023. Epub 2024 Jan 22.
7
Glucose regulates hypoxia-induced NLRP3 inflammasome activation in macrophages.
J Cell Physiol. 2020 Oct;235(10):7554-7566. doi: 10.1002/jcp.29659. Epub 2020 Mar 1.
8
The two pore potassium channel THIK-1 regulates NLRP3 inflammasome activation.
Glia. 2022 Jul;70(7):1301-1316. doi: 10.1002/glia.24174. Epub 2022 Mar 30.
9
The purinergic 2X7 receptor participates in renal inflammation and injury induced by high-fat diet: possible role of NLRP3 inflammasome activation.
J Pathol. 2013 Nov;231(3):342-53. doi: 10.1002/path.4237. Epub 2013 Sep 3.
10
P2X receptor inhibition attenuated sympathetic nerve sprouting after myocardial infarction via the NLRP3/IL-1β pathway.
J Cell Mol Med. 2017 Nov;21(11):2695-2710. doi: 10.1111/jcmm.13185. Epub 2017 May 4.
引用本文的文献
1
The Analgesic Effect of NLRP3 Inflammasome in the Relief of Inflammatory Pain by Electroacupuncture: A Systematic Review and Meta-Analysis of Animal Studies.
J Pain Res. 2025 Aug 27;18:4413-4430. doi: 10.2147/JPR.S534757. eCollection 2025.
2
The NLRP3 inflammasome in urogenital cancers: structure, dual function, and therapeutic potential.
Front Oncol. 2025 Jul 11;15:1593774. doi: 10.3389/fonc.2025.1593774. eCollection 2025.
3
A lipid plug affects K6.1(TWIK-2) function.
bioRxiv. 2025 Jun 15:2025.06.11.659167. doi: 10.1101/2025.06.11.659167.
4
Dimethyl fumarate improves sepsis-induced acute lung injury by inhibiting STING-mediated ferroptosis.
J Bioenerg Biomembr. 2025 Jul 5. doi: 10.1007/s10863-025-10068-9.
5
ACPA-Induced ATP release and K efflux trigger NLRP3 inflammasome activation in rheumatoid arthritis.
Cell Commun Signal. 2025 Jul 1;23(1):302. doi: 10.1186/s12964-025-02331-8.
6
NLRP3 Inflammasome Activation in Liver Disorders: From Molecular Pathways to Therapeutic Strategies.
J Inflamm Res. 2025 Jun 24;18:8277-8294. doi: 10.2147/JIR.S532908. eCollection 2025.
7
Effect of Potassium-Magnesium Sulfate on Intestinal Dissociation and Absorption Rate, Immune Function, and Expression of NLRP3 Inflammasome, Aquaporins and Ion Channels in Weaned Piglets.
Animals (Basel). 2025 Jun 13;15(12):1751. doi: 10.3390/ani15121751.
8
Tolerance to Lung Infection in TWIK2 K Efflux Mediated Macrophage Trained Immunity.
bioRxiv. 2025 May 28:2025.05.25.655979. doi: 10.1101/2025.05.25.655979.
9
Eukaryotic ADCY7 catalyzes the production of c-di-AMP to activate the NLRP3 inflammasome.
Nat Chem Biol. 2025 May 26. doi: 10.1038/s41589-025-01919-y.
10
Macrophage Notch1 drives septic cardiac dysfunction by impairing mitophagy and promoting NLRP3 activation.
Biol Direct. 2025 May 26;20(1):65. doi: 10.1186/s13062-025-00657-4.
本文引用的文献
1
A voltage-dependent K channel in the lysosome is required for refilling lysosomal Ca stores.
J Cell Biol. 2017 Jun 5;216(6):1715-1730. doi: 10.1083/jcb.201612123. Epub 2017 May 3.
2
Recombinant tandem of pore-domains in a Weakly Inward rectifying K channel 2 (TWIK2) forms active lysosomal channels.
Sci Rep. 2017 Apr 5;7(1):649. doi: 10.1038/s41598-017-00640-8.
3
Inflammasomes: Key Mediators of Lung Immunity.
Annu Rev Physiol. 2017 Feb 10;79:471-494. doi: 10.1146/annurev-physiol-021115-105229.
4
K Efflux-Independent NLRP3 Inflammasome Activation by Small Molecules Targeting Mitochondria.
Immunity. 2016 Oct 18;45(4):761-773. doi: 10.1016/j.immuni.2016.08.010. Epub 2016 Sep 27.
5
Inflammasomes: mechanism of assembly, regulation and signalling.
Nat Rev Immunol. 2016 Jul;16(7):407-20. doi: 10.1038/nri.2016.58. Epub 2016 Jun 13.
6
Macrophage activation and polarization modify P2X7 receptor secretome influencing the inflammatory process.
Sci Rep. 2016 Mar 3;6:22586. doi: 10.1038/srep22586.
7
K+ efflux agonists induce NLRP3 inflammasome activation independently of Ca2+ signaling.
J Immunol. 2015 Apr 15;194(8):3937-52. doi: 10.4049/jimmunol.1402658. Epub 2015 Mar 11.
8
Macrophages sense and kill bacteria through carbon monoxide-dependent inflammasome activation.
J Clin Invest. 2014 Nov;124(11):4926-40. doi: 10.1172/JCI72853. Epub 2014 Oct 8.
9
TWIK-2 channel deficiency leads to pulmonary hypertension through a rho-kinase-mediated process.
Hypertension. 2014 Dec;64(6):1260-5. doi: 10.1161/HYPERTENSIONAHA.114.03406. Epub 2014 Sep 22.
10
Critical role for the NLRP3 inflammasome during acute lung injury.
J Immunol. 2014 Jun 15;192(12):5974-83. doi: 10.4049/jimmunol.1400368. Epub 2014 May 2.
Zotero 插件