BK potassium channel activity in cSiO2-induced lysosome membrane permeability and inflammation

摘要 慢性炎症是导致肺部和其他疾病的一个重要因素。一次触发 慢性炎症在职业环境中是可呼吸的结晶二氧化硅(CSiO)，因此，呈现一种 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。 二氧化碳引起大鼠巨噬细胞吞噬体膜通透性(LMP)和NLRP3炎症小体激活 肺泡巨噬细胞。激活的炎症体裂解caspase-1并通过 白介素1b(IL-1b)和白介素18(IL-18)的分泌。溶酶体在NLRP3炎性小体中的作用 它的活性及其对巨噬细胞动态平衡的贡献使其在巨噬细胞的发展中具有重要意义。 针对慢性炎症性人类健康状况的治疗目标。在溶酶体内，离子通道是 对它的功能来说是不可或缺的。本研究将探讨溶酶体K+通道在心肌梗死中的作用。 LMP及其在NLRP3介导的炎症中的作用。目前的文献表明，颗粒物诱导的 NLRP3炎症体活动与胞浆K+的减少有关，这被认为是K+从 胞浆转化为细胞外基质。然而，溶酶体K+通道对细胞毒性的降低起着重要作用。 必须考虑NLPR3炎性小体激活过程中的胞内K+。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 提出cSiO_2与溶酶体膜相互作用并启动 溶酶体膜脂有序，促进溶酶体膜BK通道活性，胞内K+，LMP， 和NLRP3炎症体活性。

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. The activated inflammasome cleaves caspase-1 and triggers inflammation through the secretion 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 must be considered. 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.