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

Nature Communications
Eman Khatib-MassalhaTsvee Lapidot

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.

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Citations

Jul 16, 2020·American Journal of Physiology. Cell Physiology·János G Filep, Amiram Ariel
Jan 8, 2021·PLoS Pathogens·Hendrik PossemiersPhilippe E Van den Steen
Feb 5, 2021·Haematologica·Orit KolletTsvee Lapidot
Jan 8, 2021·Frontiers in Oncology·Alessandro BarbatoAlessandra Romano
Apr 15, 2021·Acta Pharmacologica Sinica·Susan Wai Sum Leung, Yi Shi
Feb 19, 2021·Yeungnam University Journal of Medicine·Tae-Yoon Lee
Jun 29, 2021·Frontiers in Immunology·An-Na ChenJin Yang
Jul 27, 2021·International Reviews of Immunology·Hai-Cun ZhouHong-Bin Liu
Aug 17, 2021·Frontiers in Immunology·Indumathi ManoharanSanthakumar Manicassamy
Aug 7, 2021·Advances in Wound Care·Norifumi UraoGayathri Ganesh

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Methods Mentioned

BETA
Flow
flow cytometry
transgenic
biopsies
FACS
ELISA

Software Mentioned

MACSQuant
MACSQant
zUMI package
ImageJ
Imaris
ImageStream
Imaris Surface
Prism
R
Ensembl

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