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.
|State||Published - 15 Jul 2020|
Bibliographical noteFunding Information:
We thank S. Jung and G. Shakhar for fruitful discussions and suggestions. We thank O. Golani for her help with intravital imaging analysis and M. Goldsmith for his help with lactate measurement. This research was supported by the Israel Science Foundation (grant No. 85471/); The ISF-NSFC joint research program (grant No. 2474/16); The Asher Pertman and Wayne Pertman, and the Estate of David Levinson; The Ernest and Bonnie Beutler Research Program of Excellence in Genomic Medicine; The Cooperation Program in Cancer Research of the Deutsches Krebsforschungszentrum (DKFZ) and Israel’s Ministry of Science and Technology (MOST); The Canadian Institutes of Health Research (CIHR), the International Development Research Centre (IDRC), the Israel Science Foundation (ISF) and the Azrieli Foundation (T.L.). The imaging platform used for this research was supported by the de Picciotto-Lesser Cell Observatory and the Elsie and Marvin Dekelboum Family Foundation. This research was also supported as part of a Ph.D. funded by a Planning & Budgeting Committee of the Council of Higher Education of Israel personal grant (E.K.M.).
© 2020, The Author(s).
ASJC Scopus subject areas
- Chemistry (all)
- Biochemistry, Genetics and Molecular Biology (all)
- Physics and Astronomy (all)