Pharmacology Department, University of Virginia, Pinn Hall, 1340 Jefferson Park Avenue, Charlottesville, VA, 22908, USA.
Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
Nat Commun. 2022 Jun 9;13(1):3230. doi: 10.1038/s41467-022-30959-4.
Efficient clearance of apoptotic cells by phagocytosis, also known as efferocytosis, is fundamental to developmental biology, organ physiology, and immunology. Macrophages use multiple mechanisms to detect and engulf apoptotic cells, but the signaling pathways that regulate the digestion of the apoptotic cell cargo, such as the dynamic Ca signals, are poorly understood. Using an siRNA screen, we identify TRPM7 as a Ca-conducting ion channel essential for phagosome maturation during efferocytosis. Trpm7-targeted macrophages fail to fully acidify or digest their phagosomal cargo in the absence of TRPM7. Through perforated patch electrophysiology, we demonstrate that TRPM7 mediates a pH-activated cationic current necessary to sustain phagosomal acidification. Using mice expressing a genetically-encoded Ca sensor, we observe that phagosome maturation requires peri-phagosomal Ca-signals dependent on TRPM7. Overall, we reveal TRPM7 as a central regulator of phagosome maturation during macrophage efferocytosis.
通过吞噬作用（也称为胞葬作用）有效地清除凋亡细胞对于发育生物学、器官生理学和免疫学至关重要。巨噬细胞使用多种机制来检测和吞噬凋亡细胞，但调节凋亡细胞货物消化的信号通路（如动态 Ca 信号）知之甚少。通过 siRNA 筛选，我们确定 TRPM7 是胞葬作用过程中吞噬体成熟所必需的 Ca 传导离子通道。缺乏 TRPM7 的情况下，靶向 Trpm7 的巨噬细胞无法完全酸化或消化其吞噬体货物。通过穿孔贴片电生理学，我们证明 TRPM7 介导了维持吞噬体酸化所需的 pH 激活阳离子电流。使用表达基因编码 Ca 传感器的小鼠，我们观察到吞噬体成熟需要依赖于 TRPM7 的周质 Ca 信号。总的来说，我们揭示了 TRPM7 作为巨噬细胞胞葬作用过程中吞噬体成熟的中央调节剂。
