In vivo Cytokine Adsorption Reveals Distinct Neutrophil Mobilization Pathways during Experimental Human Endotoxemia

During acute inflammation, such as experimental human endotoxemia, circulating neutrophil counts initially decrease, followed by pronounced neutrophilia. Banded (CD16dim/CD62Lbright) and hypersegmented (CD16bright/CD62Ldim) neutrophils, which are absent in the blood during homeostasis, are rapidly mobilized. Banded and mature neutrophils are thought to be recruited from the bone marrow, while the origin of hypersegmented neutrophils remains disputed and underlying recruitment mechanisms remain to be established.

Fifteen volunteers received an intravenous bolus of bacterial lipopolysaccharide (LPS) followed by continuous infusion for 3 h. Seven were randomly assigned to additional cytokine adsorption therapy, enabling analysis of neutrophil subsets across a broad range of circulating cytokine concentrations. Blood samples were obtained at baseline and 3 h post-LPS bolus to assess neutrophil subset quantities, neutrophil surface activation markers, and plasma cytokine levels.

Circulating concentrations of pro-inflammatory cytokines (TNF, interleukin (IL)-6, CXCL8, CCL3, and CCL2) were negatively associated with circulating mature and banded neutrophil numbers, suggesting a role for these cytokines in their migration. The absence of a correlation between plasma cytokines with hypersegmented neutrophils indicates an alternative mobilization signal. In contrast to cell numbers, neutrophil activation markers positively correlated with concentrations of the various pro-inflammatory cytokines, indicating involvement of cytokines in neutrophil activation.

Circulating cytokines appear to be key drivers of mature and banded neutrophil migration, whereas this complex signal does not influence the abundance of CD62Ldim cells in peripheral blood.