Figure 1. Neutrophils encounter complex signaling environments during forward and reverse migration in vivo.

A. When tissue damage is detected, neutrophils migrate out of the vasculature in a process called transendothelial migration B. In the tissues, neutrophils engage in multi-step navigation toward sources of intermediary chemoattractants. C. Once neutrophils detect wound-derived, end-target signals, they ignore intermediary attractants. D. In the wound, neutrophils integrate multiple signals, including recruitment and retention signals, pro-inflammatory and anti-inflammatory molecules. E. Neutrophil clustering is mediated by the CXCL1/CXCL8 signaling axis F. At the wound, neutrophils mount a cytotoxic response that includes degranulation, phagocytosis, and NET formation. G. In the wound, CXCR1 is rapidly internalized, leaving CXCR2 as the primary CXCL8 receptor. CXCR2 promotes cluster dissolution. H. Macrophages secrete PGE2, which activates neutrophil EP4 receptors preventing 5-LO translocation into the nucleus. As a result, neutrophils switch from the production of LTB4 to the production of LXA4. I. Some neutrophils undergo apoptosis and efferocytosis by macrophages. J. After overcoming recruitment and retention signals, some neutrophils are randomly dispersed from the wound microenvironment. K. Once they leave the wound, neutrophils reverse migrate back toward the vasculature. L. LTB4 mediates rTEM allowing neutrophils re-enter circulation.

CXCL8

LTB4

End-Target Attractant

Retention Signal

PGE2