Kendall Rebekah L, Postma Britten, Holian Andrij
Center for Environmental Health Sciences, University of Montana, Missoula, Montana, USA.
Inhal Toxicol. 2025 Apr;37(4):173-182. doi: 10.1080/08958378.2025.2507251. Epub 2025 May 22.
Lysosomal ion channel function in macrophages contributes to the development of silica-induced inflammation. Recent studies have shown that blocking K entry into the lysosome the BK channel reduces silica-induced damage and inflammation in macrophages. This study aims to explore the mechanisms of particle-induced inflammation in BK macrophages. Bone marrow derived macrophages (BMdM) from C57BL/6 wildtype (WT) and BK mice were exposed to silica and IL-1β release and cell death assessed. The effect of BK on lysosomal pH, proteolytic activity, and cholesterol accumulation was evaluated. BK BMdM failed to demonstrate a reduction in IL-1β or cell death following silica exposure. BK BMdM had comparable lysosome function to WT suggesting a compensatory mechanism was maintaining lysosome function. BK macrophages demonstrated an upregulation of a second lysosomal potassium channel, TMEM175. Inhibition of TMEM175 activity caused an increase in lysosomal pH and reduced silica-induced cell death and IL-1β release in both BK and WT BMdM. BK BMdM did not exhibit the same phenotype seen with pharmaceutical abrogation of BK channel activity and showed no differences from WT in response to silica exposure. Upregulation of TMEM175 in BK macrophages appears to prevent changes in lysosomal pH and cholesterol accumulation. Inhibiting TMEM175 activity in both BK and WT BMdM resulted in an increase in lysosomal pH and reduced silica-induced inflammation, suggesting that reduced particle-induced cell damage and inflammation is not dependent on the activity of a single lysosomal ion channel but rather on mechanisms that elevate lysosomal pH.
巨噬细胞中的溶酶体离子通道功能有助于二氧化硅诱导的炎症发展。最近的研究表明，阻断钾离子进入溶酶体——大电导钙激活钾通道（BK通道）可减少二氧化硅诱导的巨噬细胞损伤和炎症。本研究旨在探索BK巨噬细胞中颗粒诱导炎症的机制。将来自C57BL/6野生型（WT）和BK小鼠的骨髓来源巨噬细胞（BMdM）暴露于二氧化硅，评估白细胞介素-1β（IL-1β）释放和细胞死亡情况。评估BK对溶酶体pH值、蛋白水解活性和胆固醇积累的影响。BK BMdM在暴露于二氧化硅后未能表现出IL-1β减少或细胞死亡减少的情况。BK BMdM具有与WT相当的溶酶体功能，表明存在一种补偿机制维持溶酶体功能。BK巨噬细胞表现出第二种溶酶体钾通道TMEM175的上调。抑制TMEM175活性导致溶酶体pH值升高，并减少了BK和WT BMdM中二氧化硅诱导的细胞死亡和IL-1β释放。BK BMdM未表现出与药物性废除BK通道活性相同的表型，并且在对二氧化硅暴露的反应中与WT没有差异。BK巨噬细胞中TMEM175的上调似乎可防止溶酶体pH值和胆固醇积累的变化。抑制BK和WT BMdM中的TMEM175活性均导致溶酶体pH值升高，并减少了二氧化硅诱导的炎症，这表明颗粒诱导的细胞损伤和炎症减少并不依赖于单个溶酶体离子通道的活性，而是依赖于提高溶酶体pH值的机制。
