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

Nat Commun. 2020 Jul 15;11(1):3547. doi: 10.1038/s41467-020-17402-2.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Marrow / blood supply
  • Bone Marrow Cells / immunology*
  • Bone Marrow Cells / metabolism
  • Disease Models, Animal
  • Endothelium, Vascular / metabolism
  • Female
  • Humans
  • Lactic Acid / metabolism*
  • Lipopolysaccharides / immunology
  • Male
  • Mice
  • Mice, Knockout
  • Neutrophils / immunology*
  • Neutrophils / metabolism
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*
  • Salmonella Infections / immunology*
  • Salmonella Infections / microbiology
  • Salmonella typhimurium / immunology
  • Signal Transduction / immunology

Substances

  • Hcar1 protein, mouse
  • Lipopolysaccharides
  • Receptors, G-Protein-Coupled
  • Lactic Acid

Grant support