Fig. 8: Mechanisms of lactate-induced neutrophil mobilization from the BM.

Our model suggests that enhanced lactate-produced by BM neutrophils during bacterial infection induces neutrophil mobilization by modulating metabolic signaling in BM endothelial cells. LPS binds TLR4 expressed on neutrophils that directly activates NADPH oxidase (NOX) and enhances glucose uptake via a glucose transporter 1a. Glucose in turn, is converted to pyruvate by the glycolysis pathway 1b. NOX activity leads to ROS production (2) which elevates HIF-1α expression. HIF-1α in turn, induces downstream expression of LDHA that converts pyruvate to lactate 3a. HIF-1α also up-regulates the lactate transporter MCT4 3b to allow lactate release (4). Under steady-state conditions, surface VE–cadherin on endothelial cells (ECs) is highly expressed, which maintains the endothelial barrier integrity with low permeability (a). During inflammation (b), lactate released from BM neutrophils binds to GPR81 on sinusoidal BM endothelial cells 5a, activates G_i protein and thereby reduces cAMP/Epac1 activity 5b. Consequently, lactate via GPR81 signaling decreases surface VE–cadherin expression (5c), leading to higher BM vascular permeability (6). In addition, lactate elevates CXCL1 and G-CSF levels (produced by different cells including ECs^50,52) also in a GPR81-independent manner 7a with more moderate increases in CXCL2 levels in WT mice (most probably produced by BM neutrophils⁵⁰). Lactate-induced elevation of CXCL1, CXCL2, and G-CSF downregulates surface CXCR2 expression on PB neutrophils 7b facilitating neutrophil mobilization (8). Taken together, LPS-induced lactate promotes rapid neutrophil mobilization from the BM to the blood (8) preferentially via BM GPR81/VE–cadherin-dependent (5–6) and also by GPR81-independent (7) pathways.