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：
10463030
负责人：
Andrij Holian
金额：
$ 22.2万
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/10463030
关键词：
Address Alveolar Macrophages Applied Research Autoimmune Diseases CASP1 gene Cations Cell Death Cell Membrane Permeability Cholesterol Chronic 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 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 fundamental research improved in vivo inhibitor interest large-conductance calcium-activated potassium channels lysosome membrane macrophage 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.

抽象的慢性炎症是肺部疾病和其他疾病的重要诱因之一。炎症是职业环境中可吸入的结晶二氧化硅 (cSiO2)，因此，提供了一种有用的方法模型来研究未解决的、溶酶体功能障碍介导的 cSiO2 引起的炎症的机制。肺泡中吞噬溶酶体膜透化 (LMP) 和 NLRP3 炎性体激活激活的炎症小体通过 caspase-1 介导的成熟引发炎症。白细胞介素 1b (IL-1b) 和白细胞介素 18 (IL-18) 溶酶体在 NLRP3 炎症小体活性中的作用及其作用。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对于慢性炎症人类健康状况，溶酶体中的离子通道是不可或缺的。本研究将探讨溶酶体钾 (K+) 通道在 LMP 中的作用及其功能。有助于 NLRP3 介导的炎症。目前的文献表明，颗粒物诱导的 NLRP3。炎症小体活性与胞质 K+ 的减少相关，这被认为是 K+ 从胞质中流出然而，溶酶体 K+ 通道对胞质 K+ 减少的贡献。本研究将评估 NLPR3 炎症小体的激活，我们的初步结果表明 K+。在 LMP 之前通过溶酶体大电导钾 (BK) 通道进入溶酶体 NLRP3 炎性体活性阻断溶酶体 BK 通道活性可减少 cSiO2 诱导的细胞死亡。和 IL-1b 释放，表明溶酶体离子通道参与了 LMP 的机制。解决了 cSiO2 与溶酶体膜相互作用并引发溶酶体变化的假设膜脂质顺序并促进溶酶体 BK 通道活性、胞质 K+、LMP 和 NLRP3 减少炎症小体活动。