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

Author

Listed:
  • Michael S. Schappe

    (University of Virginia
    Harvard Medical School)

  • 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
    University of Virginia
    University of Virginia)

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.

Suggested Citation

  • 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 & Bimal N. Desai, 2022. "Efferocytosis requires periphagosomal Ca2+-signaling and TRPM7-mediated electrical activity," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30959-4
    DOI: 10.1038/s41467-022-30959-4
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    References listed on IDEAS

    as
    1. Michael R. Elliott & Faraaz B. Chekeni & Paul C. Trampont & Eduardo R. Lazarowski & Alexandra Kadl & Scott F. Walk & Daeho Park & Robin I. Woodson & Marina Ostankovich & Poonam Sharma & Jeffrey J. Lys, 2009. "Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance," Nature, Nature, vol. 461(7261), pages 282-286, September.
    2. Mathieu Houde & Sylvie Bertholet & Etienne Gagnon & Sylvain Brunet & Guillaume Goyette & Annie Laplante & Michael F. Princiotta & Pierre Thibault & David Sacks & Michel Desjardins, 2003. "Phagosomes are competent organelles for antigen cross-presentation," Nature, Nature, vol. 425(6956), pages 402-406, September.
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