Lysosomal BK channel regulates cSiO2-induced macrophage inflammation

摘要 慢性炎症是导致肺部和其他疾病的一个重要因素。慢性病的一个诱因 炎症在职业环境中是可呼吸的结晶二氧化硅(CSiO)，因此，提供了一种有用的 模型研究未解决的、溶酶体功能障碍介导的炎症的机制。二氧化硅成因 肺泡吞噬酶体膜通透性与NLRP3炎性小体激活 巨噬细胞。激活的炎症体通过caspase-1介导的成熟 白介素1b(IL-1b)和白介素18(IL-18)。溶酶体在NLRP3炎性小体活动中的作用及其意义 巨噬细胞动态平衡的贡献使其在治疗靶点的开发中受到极大关注 适用于慢性炎症性人体健康状况。在溶酶体中，离子通道是其不可缺少的 功能。本研究将探讨溶酶体钾(K)通道在LMP中的作用及其机制。 有助于NLRP3介导的炎症。目前的文献表明，颗粒物诱导的NLRP3 炎性小体活动与胞液K的减少有关，后者被认为是K从胞浆中流出 细胞外基质。然而，溶酶体K通道在细胞内K降低中的作用 本研究将对NLPR3炎症体的激活进行评估。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炎症体活性。阻断溶酶体BK通道活性可减少cSiO_2诱导的细胞死亡 IL-1b的释放，提示溶酶体离子通道参与了LMP的发病机制。这个项目将 说明cSiO_2与溶酶体膜相互作用并启动溶酶体膜变化的假设。 膜脂有序并促进溶酶体BK通道活性，胞浆K、LMP和NLRP3减少 炎性小体活动。

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.