During their recruitment into organs, neutrophils initially adhere to the vascular wall and then transmigrate across the endothelium into the target site (Ley et al., 2007). These events have been studied extensively, and have revealed a cascade of molecular interactions between neutrophils and endothelial cells (Springer, 1994; Ley et al., 2007; Zarbock and Ley, 2009).
In contrast, relatively little is known about the dynamics and molecular cues that direct neutrophil navigation through the interstitial space toward a focus of damaged tissue. Recent intravital imaging studies including infection models in the skin, lymph nodes, and lungs have bestowed us with first clues as to how neutrophils behave in the extravascular space in vivo (Chtanova et al., 2008; Peters et al., 2008; Graham et al., 2009; Kreisel et al., 2010). These studies have shown that neutrophils rapidly accumulate at sites of pathogen deposition. There, they form small, transient, or larger, more persistent “swarms” with some neutrophils containing pathogens.
These findings suggest that specific guidance cues for neutrophils must be established within injured tissues that facilitate their prompt attraction to a focus of stressed or damaged cells. Indeed, a recent study using in vivo confocal microscopy following sterile liver injury has unraveled several molecular pathways involved in neutrophil sensing of necrotic cells, including intravascular chemokine gradients and formyl-peptide signals released by necrotic cells (McDonald et al., 2010). Another study showed that neutrophil cluster formation during lung injury depends on monocytes (Kreisel et al. 2010). However, the definition of the precise cascade of events and molecular cues that guide neutrophils through the extravascular space within peripheral tissues such as the dermis requires further experimentation.
