Efferocytosis requires periphagosomal Ca2+-signaling and TRPM7-mediated electrical activity

Michael S. Schappe, Marta E. Stremska, Gregory W. Busey, Taylor K. Downs, Philip V. Seegren, Suresh K. Mendu, Zachary Flegal, Catherine A. Doyle, Eric J. Stipes and Bimal N. Desai ()
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Michael S. Schappe: University of Virginia
Marta E. Stremska: University of Virginia
Gregory W. Busey: University of Virginia
Taylor K. Downs: University of Virginia
Philip V. Seegren: University of Virginia
Suresh K. Mendu: University of Virginia
Zachary Flegal: University of Virginia
Catherine A. Doyle: University of Virginia
Eric J. Stipes: University of Virginia
Bimal N. Desai: University of Virginia

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract 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 Ca2+ signals, are poorly understood. Using an siRNA screen, we identify TRPM7 as a Ca2+-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 Ca2+ sensor, we observe that phagosome maturation requires peri-phagosomal Ca2+-signals dependent on TRPM7. Overall, we reveal TRPM7 as a central regulator of phagosome maturation during macrophage efferocytosis.

Date: 2022
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DOI: 10.1038/s41467-022-30959-4

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