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

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, Isabell Brandenburger, Asaf Spiegel, Ziv Shulman, Zachary Gerhart-Hines, Shalev Itzkovitz, Matthias Gunzer, Stefan Offermanns, Ronen Alon, Amiram Ariel and Tsvee Lapidot ()
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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
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

Nature Communications, 2020, vol. 11, issue 1, 1-18

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-17402-2

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