Reverse Migration of Neutrophils: Where, When, How, and Why?

Neutrophil migration to injured and pathogen-infected tissues is a fundamental component of innate immunity. An array of cellular and molecular events mediate this response to collectively guide neutrophils out of the vasculature and towards the core of the ensuing inflammatory reaction where they exert effector functions. Advances in imaging modalities have revealed that neutrophils can also exhibit motility away from sites of inflammation and injury, although it is unclear under what circumstances this reverse migration is a physiological protective response, and when it has pathophysiological relevance. Here we review different types of neutrophil reverse migration and discuss the current understanding of the associated mechanisms. In this context we propose clarifications to the existing terminology used to describe the many facets of neutrophil reverse migration.

TrendsNeutrophils can exhibit abluminal-to-luminal motility through endothelial cells (rTEM) and reverse interstitial migration (rIM) in models of inflammation. Emerging data suggest that the former can mediate systemic dissemination of a local inflammatory response whereas the latter is a protective physiological event that facilitates inflammation resolution.In models of inflammation, neutrophil rTEM is enhanced and reduced in EC JAM-C−/− and neutrophil elastase (NE)−/− mice, respectively, demonstrating novel roles of these molecules in regulation of neutrophil trafficking.Neutrophil rIM is suppressed by genetic activation of the HIF pathway in zebrafish, an intervention that causes a delay in inflammation resolution.Targeting neutrophil reverse migration represents a novel approach for development of drugs aimed at modulating inflammation.