Lysosomal BK channel regulates cSiO2-induced macrophage inflammation

摘要 慢性炎症是肺部疾病和其他疾病的重要促成因素。慢性病的诱因之一 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炎症的机制。 cSiO2 原因 肺泡中吞噬溶酶体膜透化 (LMP) 和 NLRP3 炎性体激活 巨噬细胞。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 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 用于慢性炎症的人类健康状况。在溶酶体中，离子通道对于溶酶体的运作是不可或缺的。 功能。本研究将探讨溶酶体钾 (K) 通道在末次月经中的作用以及它如何发挥作用。 有助于 NLRP3 介导的炎症。目前的文献表明，颗粒物诱导的 NLRP3 炎症小体活性与细胞溶质 K 的减少相关，这被认为是 K 从细胞溶质流出 至细胞外基质。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 和 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。该项目将 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，减少胞质 K 、LMP 和 NLRP3 炎症小体活动。

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.