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Lysosomal BK channel regulates cSiO2-induced macrophage inflammation

溶酶体 BK 通道调节 cSiO2 诱导的巨噬细胞炎症

基本信息

批准号：
10618324
负责人：
Andrij Holian
金额：
$ 18.5万
依托单位：
UNIVERSITY OF MONTANA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-05 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10618324
关键词：
Acceleration Address Alveolar Macrophages Applied Research Autoimmune Diseases CASP1 gene Cations Cell Death Induction Cell Membrane Permeability Cholesterol Chronic Cytosol Data Disease Environment Exposure to Extracellular Matrix Fluorescence Spectroscopy Functional disorder Health Homeostasis Hour Human Hydroxychloroquine IL18 gene Imipramine In Vitro Incubated Inflammasome Inflammation Inflammatory Interleukins Ion Channel Knowledge Laboratories Lipids Liposomes Literature Lumen of the Lysosome Lung Lysosomes Macrophage 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 cytotoxicity fundamental research improved in vivo inhibitor interest large-conductance calcium-activated potassium channels lysosome membrane magnetic beads novel particle paxilline prevent response therapeutic development therapeutic target therapeutically effective trend

项目摘要

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. Activated inflammasome triggers inflammation through caspase-1 mediated maturation 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 will be evaluated in this study. 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。慢性病的一个诱因炎症是可吸入的结晶二氧化硅（cSiO 2）在职业环境中，因此，提出了一个有用的模型来研究未解决的溶酶体功能障碍介导的炎症的机制。cSiO 2导致肺泡巨噬细胞吞噬溶酶体膜透化（LMP）和NLRP 3炎性小体激活巨噬细胞活化的炎性小体通过caspase-1介导的细胞成熟触发炎症反应。白细胞介素1b（IL-1b）和白细胞介素18（IL-18）。溶酶体在NLRP 3炎性小体活性中的作用及其机制对巨噬细胞稳态的贡献使其在治疗靶点的开发中具有重要意义用于慢性炎症性人类健康状况。在溶酶体内，离子通道是其不可或缺的。功能本研究将探讨溶酶体钾（K+）通道在LMP中的作用，以及它如何影响LMP的功能。导致NLRP 3介导的炎症。目前的文献表明，颗粒诱导的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+从细胞溶质流出与细胞外基质的联系然而，溶酶体K+通道对细胞质K+降低的贡献，本研究将评价NLPR 3炎性小体活化。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cSiO 2与溶酶体膜相互作用并引发溶酶体变化的假设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的减少炎性小体活性。