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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：
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.

摘要