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Lactate released by inflammatory bone marrow neutrophils induces their mobilization via endothelial GPR81 signaling

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Listed:
  • Eman Khatib-Massalha

    (Department of Immunology, Weizmann Institute of Science)

  • Suditi Bhattacharya

    (Department of Immunology, Weizmann Institute of Science)

  • Hassan Massalha

    (Department of Molecular Cell Biology, Weizmann Institute of Science)

  • Adi Biram

    (Department of Immunology, Weizmann Institute of Science)

  • Karin Golan

    (Department of Immunology, Weizmann Institute of Science)

  • Orit Kollet

    (Department of Immunology, Weizmann Institute of Science)

  • Anju Kumari

    (Department of Immunology, Weizmann Institute of Science)

  • Francesca Avemaria

    (Department of Immunology, Weizmann Institute of Science)

  • Ekaterina Petrovich-Kopitman

    (Department of Immunology, Weizmann Institute of Science
    Life science Core facilities, Weizmann Institute of Science)

  • Shiri Gur-Cohen

    (Department of Immunology, Weizmann Institute of Science)

  • Tomer Itkin

    (Department of Immunology, Weizmann Institute of Science)

  • Isabell Brandenburger

    (Department of Pharmacology, Max-Planck-Institute for Heart and Lung Research)

  • Asaf Spiegel

    (Department of Immunology, Weizmann Institute of Science)

  • Ziv Shulman

    (Department of Immunology, Weizmann Institute of Science)

  • Zachary Gerhart-Hines

    (University of Copenhagen)

  • Shalev Itzkovitz

    (Department of Molecular Cell Biology, Weizmann Institute of Science)

  • Matthias Gunzer

    (University Hospital, University Duisburg-Essen)

  • Stefan Offermanns

    (Department of Pharmacology, Max-Planck-Institute for Heart and Lung Research)

  • Ronen Alon

    (Department of Immunology, Weizmann Institute of Science)

  • Amiram Ariel

    (University of Haifa)

  • Tsvee Lapidot

    (Department of Immunology, Weizmann Institute of Science)

Abstract

Neutrophils provide first line of host defense against bacterial infections utilizing glycolysis for their effector functions. How glycolysis and its major byproduct lactate are triggered in bone marrow (BM) neutrophils and their contribution to neutrophil mobilization in acute inflammation is not clear. Here we report that bacterial lipopolysaccharides (LPS) or Salmonella Typhimurium triggers lactate release by increasing glycolysis, NADPH-oxidase-mediated reactive oxygen species and HIF-1α levels in BM neutrophils. Increased release of BM lactate preferentially promotes neutrophil mobilization by reducing endothelial VE-Cadherin expression, increasing BM vascular permeability via endothelial lactate-receptor GPR81 signaling. GPR81−/− mice mobilize reduced levels of neutrophils in response to LPS, unless rescued by VE-Cadherin disrupting antibodies. Lactate administration also induces release of the BM neutrophil mobilizers G-CSF, CXCL1 and CXCL2, indicating that this metabolite drives neutrophil mobilization via multiple pathways. Our study reveals a metabolic crosstalk between lactate-producing neutrophils and BM endothelium, which controls neutrophil mobilization under bacterial infection.

Suggested Citation

  • Eman Khatib-Massalha & Suditi Bhattacharya & Hassan Massalha & Adi Biram & Karin Golan & Orit Kollet & Anju Kumari & Francesca Avemaria & Ekaterina Petrovich-Kopitman & Shiri Gur-Cohen & Tomer Itkin &, 2020. "Lactate released by inflammatory bone marrow neutrophils induces their mobilization via endothelial GPR81 signaling," Nature Communications, Nature, vol. 11(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17402-2
    DOI: 10.1038/s41467-020-17402-2
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    References listed on IDEAS

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    1. Anjali P. Kusumbe & Saravana K. Ramasamy & Ralf H. Adams, 2014. "Coupling of angiogenesis and osteogenesis by a specific vessel subtype in bone," Nature, Nature, vol. 507(7492), pages 323-328, March.
    2. Robert Haas & Joanne Smith & Vidalba Rocher-Ros & Suchita Nadkarni & Trinidad Montero-Melendez & Fulvio D’Acquisto & Elliot J Bland & Michele Bombardieri & Costantino Pitzalis & Mauro Perretti & Feder, 2015. "Lactate Regulates Metabolic and Pro-inflammatory Circuits in Control of T Cell Migration and Effector Functions," PLOS Biology, Public Library of Science, vol. 13(7), pages 1-24, July.
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