TY - JOUR
T1 - Lactate released by inflammatory bone marrow neutrophils induces their mobilization via endothelial GPR81 signaling
AU - Khatib-Massalha, Eman
AU - Bhattacharya, Suditi
AU - Massalha, Hassan
AU - Biram, Adi
AU - Golan, Karin
AU - Kollet, Orit
AU - Kumari, Anju
AU - Avemaria, Francesca
AU - Petrovich-Kopitman, Ekaterina
AU - Gur-Cohen, Shiri
AU - Itkin, Tomer
AU - Brandenburger, Isabell
AU - Spiegel, Asaf
AU - Shulman, Ziv
AU - Gerhart-Hines, Zachary
AU - Itzkovitz, Shalev
AU - Gunzer, Matthias
AU - Offermanns, Stefan
AU - Alon, Ronen
AU - Ariel, Amiram
AU - Lapidot, Tsvee
N1 - Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85088021818&partnerID=8YFLogxK
U2 - 10.1038/s41467-020-17402-2
DO - 10.1038/s41467-020-17402-2
M3 - Article
C2 - 32669546
AN - SCOPUS:85088021818
SN - 2041-1723
VL - 11
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 3547
ER -
