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P-selectin-dependent leukocyte adhesion is governed by endolysosomal two-pore channel 2.

Author information

Affiliations

  • 1. Research Group Cellular Biochemistry - Regulatory Mechanisms of Inflammation, Institute of Molecular Virology, Center for Molecular Biology of Inflammation, University of Muenster (formerly Research Group Regulatory Mechanisms of Inflammation, Institute of Medical Biochemistry, Center for Molecular Biology of Inflammation, University of Muenster), von-Esmarch-Strasse 56, 48149 Muenster, Germany.
      Authors
    • Goretzko J 1
    • Pauels I 1
    • Heitzig N 1
    • Schloer S 1
    • Rescher U 1
    (5 authors)
  • 2. Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Muenster, Albert Schweitzer Campus 1, A1, 48149 Muenster, Germany.
      Authors
    • Thomas K 2
    • Kardell M 2
    • Rossaint J 2
    (3 authors)
  • 3. Institute of Medical Biochemistry, Center for Molecular Biology of Inflammation, University of Muenster, von-Esmarch-Strasse 56, 48149 Muenster, Germany.
      Authors
    • Naß J 3
    • Linard Matos AL 3
    • Gerke V 3
    (3 authors)
  • 4. Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilians-University, Nussbaumstrasse 26, 80336 Munich, Germany.
      Authors
    • Krogsaeter EK 4
    • Spix B 4
    (2 authors)
  • 5. Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians-University, Butenandtstrasse 5-13, 81377 Munich, Germany.
      Authors
    • Leser C 5
    • Bracher F 5
    (2 authors)
    • Show all (7)

ORCIDs linked to this article

Cell Reports, 30 Nov 2023, 42(12):113501
https://doi.org/10.1016/j.celrep.2023.113501 PMID: 38039128 

Abstract 

Upon proinflammatory challenges, endothelial cell surface presentation of the leukocyte receptor P-selectin, together with the stabilizing co-factor CD63, is needed for leukocyte capture and is mediated via demand-driven exocytosis from the Weibel-Palade bodies that fuse with the plasma membrane. We report that neutrophil recruitment to activated endothelium is significantly reduced in mice deficient for the endolysosomal cation channel TPC2 and in human primary endothelial cells with pharmacological TPC2 block. We observe less CD63 signal in whole-mount stainings of proinflammatory-activated cremaster muscles from TPC2 knockout mice. We find that TPC2 is activated and needed to ensure the transfer of CD63 from endolysosomes via Weibel-Palade bodies to the plasma membrane to retain P-selectin on the cell surface of human primary endothelial cells. Our findings establish TPC2 as a key element to leukocyte interaction with the endothelium and a potential pharmacological target in the control of inflammatory leukocyte recruitment.

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Read article at publisher's site: https://doi.org/10.1016/j.celrep.2023.113501

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