Figure 3.

Neutrophil recruitment in the liver. (A) Sterile inflammatory stimuli. (1) During sterile inflammation, DAMPs are released from apoptotic ECs or cells in the tissue. DAMPs can directly activate neutrophils via interaction with TLR9 or stimulate KCs to produce inflammatory mediators such as IL-1β. (2) In turn, IL-1β upregulates ICAM-1 expression on the sinusoids, resulting in the adhesion of neutrophils mediated by ICAM-1-Mac-1 interaction. (3) KCs also release CXCL2, and create a gradient that increases toward the site of injury, guiding the neutrophils. This gradient starts ~650 μm and ends at 100–150 μm away from the injury site. (4) From here on, neutrophils are guided by platelets and a formyl-peptide gradient (FPG) (released by the endothelium), in a Mac-1 and FPR1-dependen manner, respectively. (B) Pathological inflammatory stimulus. (1) During endotoxemia or Gram-negative sepsis, high levels of LPS stimulate KCs and ECs to produce large amounts of the anti-inflammatory cytokine IL-10. (2) The exposure of neutrophils to high levels of IL-10 results in down regulation of Mac-1 surface expression, yielding CD44 as the dominant adhesion molecule for recruitment. (3) CD44 then interacts with the HA/SHAP complex on the endothelium mediating the adhesion process, (4) eventually leading to neutrophil extravasation. CXCL2, Chemokine (C-X-C motif) ligand 2; CXCR2, Chemokine (C-X-C motif) receptor 2; DAMP, Damage-associated molecular pattern molecules; EC, Endothelial cell; FPG, Formyl-peptide gradient; FPR1, Formyl peptide receptor 1; HA, Hyaluronic acid; ICAM-1, Intercellular adhesion molecule-1; IL, Interleukin; KC, Kupffer cell; LPS, Lipopolysaccharide; Mac-1, Macrophage-1 antigen; SHAP, Serum-derived hyaluronan-associated protein; TLR9, Toll-like receptor 9.