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

Nature communications (2020-07-17)
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, Tsvee 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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Lipopolysaccharides from Escherichia coli O111:B4, purified by phenol extraction
Sigma-Aldrich
Tamoxifen, ≥99%
Sigma-Aldrich
Sodium oxamate, ≥98%
Sigma-Aldrich
2-Deoxy-2-[(7-nitro-2,1,3-benzoxadiazol-4-yl)amino]-D-glucose, ≥97% (HPLC)