BK potassium channel activity in cSiO2-induced lysosome membrane permeability and inflammation

BK 钾通道活性在 cSiO2 诱导的溶酶体膜通透性和炎症中的作用

• 批准号: 10314772
• 负责人: Rebekah Kendall
• 金额: $ 3.78万
• 依托单位: UNIVERSITY OF MONTANA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10314772
• 关键词: Address; Alveolar Macrophages; Autoimmune Diseases; Bone Marrow; CASP1 gene; Cations; Cell Death; Cell Membrane Permeability; Cholesterol; Chronic; Cleaved cell; Cytosol; Data; Disease; Environment; Exposure to; Extracellular Matrix; Fluorescence Spectroscopy; Functional disorder; Health; Homeostasis; Hour; Human; Hydroxychloroquine; Imipramine; In Vitro; Incubated; Inflammasome; Inflammation; Inflammatory; Interleukin-18; Interleukins; Ion Channel; Knock-out; Knowledge; Laboratories; Lead; Lipids; Liposomes; Literature; Lumen of the Lysosome; Lung; Lysosomes; Malignant neoplasm of lung; Measures; Mediating; Membrane; Membrane Lipids; Membrane Potentials; Modeling; Movement; Occupational; Occupational Exposure; Particulate; Phagolysosome; Pharmaceutical Preparations; Pharmacologic Substance; Potassium; Potassium Channel; Prevalence; Regulation; Research; Resolution; Risk; Role; Side; Signal Transduction; Silicon Dioxide; Silicosis; Techniques; Testing; Time; Tuberculosis; Work; amphiphilicity; channel blockers; chronic inflammatory disease; crystallinity; cytotoxicity; improved; in vivo; inhibitor/antagonist; interest; large-conductance calcium-activated potassium channels; lysosome membrane; macrophage; magnetic beads; novel; particle; paxilline; prevent; therapeutic development; therapeutic target; therapeutically effective; trend

Abstract Chronic inflammation is a significant contributing factor to pulmonary and other diseases. One trigger of chronic inflammation is respirable crystalline silica (cSiO2) in occupational settings, and, therefore, presents a useful model to investigate the mechanisms of unresolved, lysosome dysfunction-mediated inflammation. cSiO2 causes phagolysosomal membrane permeabilization (LMP) and NLRP3 inflammasome activation in alveolar macrophages. The activated inflammasome cleaves caspase-1 and triggers inflammation through the secretion of interleukin 1b (IL-1b) and interleukin 18 (IL-18). The lysosome’s role in NLRP3 inflammasome activity and its contributions to macrophage homeostasis make it of significant interest in the development of therapeutic targets for chronic inflammatory human health conditions. Within the lysosome, ion channels are indispensable to its function. This research will investigate the role of the lysosomal potassium (K+) channel in LMP and how it contributes to NLRP3-mediated inflammation. Current literature shows that particulate-induced NLRP3 inflammasome activity correlates to a decrease in cytosolic K+, which is assumed to be K+ efflux from the cytosol to the extracellular matrix. However, the contribution of lysosomal K+ channels to the decrease of cytosolic K+ in NLPR3 inflammasome activation must be considered. Our preliminary results indicate that K+ movement into the lysosome through the lysosomal big conductance potassium (BK) channel precedes LMP and NLRP3 inflammasome activity. Blocking lysosomal BK channel activity reduces cSiO2-induced cell death and IL-1b release, suggesting lysosomal ion channel involvement in the mechanisms in LMP. This project will address the hypothesis that cSiO2 interacts with the lysosomal membrane and initiates changes in the lysosomal membrane lipid order and promotes lysosomal BK channel activity, a decrease in cytosolic K+, LMP, and NLRP3 inflammasome activity.

摘要 慢性炎症是肺部和其他疾病的重要促成因素。一个触发器 慢性炎症是职业环境中的可吸入结晶二氧化硅（cSiO 2），因此， 研究未解决的溶酶体功能障碍介导的炎症机制的有用模型。 cSiO 2引起小鼠中吞噬溶酶体膜透化（LMP）和NLRP 3炎性小体活化。 肺泡巨噬细胞活化的炎性小体切割半胱天冬酶-1，并通过 分泌白细胞介素1b（IL-1b）和白细胞介素18（IL-18）。溶酶体在NLRP 3炎性小体中的作用 活性及其对巨噬细胞稳态的贡献使其在巨噬细胞的发展中具有重要意义。 慢性炎症性人类健康状况的治疗靶点。在溶酶体内，离子通道 它的功能不可或缺。本研究将探讨溶酶体钾（K+）通道在 LMP及其如何促进NLRP 3介导的炎症。目前的文献表明， NLRP 3炎性小体活性与细胞溶质K+的减少相关，这被认为是K+从细胞中流出。 细胞质转化为细胞外基质。然而，溶酶体K+通道对降低细胞凋亡的贡献是有限的。 必须考虑NLPR 3炎性体激活中的细胞溶质K+。我们的初步结果表明，K+ 通过溶酶体大电导钾（BK）通道进入溶酶体的运动先于LMP 和NLRP 3炎性体活性。阻断溶酶体BK通道活性减少cSiO 2诱导的细胞死亡 和IL-1b的释放，提示溶酶体离子通道参与LMP的机制。该项目将 解决假设cSiO 2与溶酶体膜相互作用，并启动变化， 溶酶体膜脂质秩序和促进溶酶体BK通道活性，细胞溶质K+，LMP， 和NLRP 3炎性体活性。