P-selectin-dependent leukocyte adhesion is governed by endolysosomal two-pore channel 2
Jonas Goretzko,
Inga Pauels,
Nicole Heitzig,
Katharina Thomas,
Marina Kardell,
Johannes Naß,
Einar Kleinhans Krogsaeter,
Sebastian Schloer,
Barbara Spix,
Anna Lívia Linard Matos,
Charlotte Leser,
Tristan Wegner,
Frank Glorius,
Franz Bracher,
Volker Gerke,
Jan Rossaint,
Christian Grimm,
Ursula Rescher
Affiliations
Jonas Goretzko
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
Inga Pauels
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
Nicole Heitzig
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
Katharina Thomas
Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Muenster, Albert Schweitzer Campus 1, A1, 48149 Muenster, Germany
Marina Kardell
Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Muenster, Albert Schweitzer Campus 1, A1, 48149 Muenster, Germany
Johannes Naß
Institute of Medical Biochemistry, Center for Molecular Biology of Inflammation, University of Muenster, von-Esmarch-Strasse 56, 48149 Muenster, Germany
Einar Kleinhans Krogsaeter
Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilians-University, Nussbaumstrasse 26, 80336 Munich, Germany
Sebastian Schloer
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
Barbara Spix
Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilians-University, Nussbaumstrasse 26, 80336 Munich, Germany
Anna Lívia Linard Matos
Institute of Medical Biochemistry, Center for Molecular Biology of Inflammation, University of Muenster, von-Esmarch-Strasse 56, 48149 Muenster, Germany
Charlotte Leser
Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians-University, Butenandtstrasse 5-13, 81377 Munich, Germany
Tristan Wegner
Institute of Organic Chemistry, University of Muenster, Corrensstrasse 40, 48149 Muenster, Germany
Frank Glorius
Institute of Organic Chemistry, University of Muenster, Corrensstrasse 40, 48149 Muenster, Germany
Franz Bracher
Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians-University, Butenandtstrasse 5-13, 81377 Munich, Germany
Volker Gerke
Institute of Medical Biochemistry, Center for Molecular Biology of Inflammation, University of Muenster, von-Esmarch-Strasse 56, 48149 Muenster, Germany
Jan Rossaint
Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Muenster, Albert Schweitzer Campus 1, A1, 48149 Muenster, Germany
Christian Grimm
Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilians-University, Nussbaumstrasse 26, 80336 Munich, Germany; Immunology, Infection and Pandemic Research IIP, Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, 60596 Frankfurt am Main, Germany
Ursula Rescher
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; Corresponding author
Summary: 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.
