Neutrophils re-entering the circulation from a primary site of inflammation: Physiological or pathological?

Neutrophils contribute to the killing and clearance of pathogens as well as initiate inflammation resolution and tissue repair processes. Furthermore, the established phenotypic and functional diversity of neutrophils have markedly extended the physiological and pathological roles of these myeloid cells. Building on the developing concept of neutrophil heterogeneity in disease settings, and significant mechanistic and pathophysiological data from the applicant, the present project aims to acquire an in-depth understanding of one population of disease-inducing neutrophils, namely neutrophils that have exhibited reverse transendothelial cells migration (rTEM). This phenomenon describes cells that initiate diapedesis, engage with endothelial cell (EC) junctions but then exhibit retrograde motility and re-enter the vascular lumen. Crucially, we have ample evidence that rTEM bestows an activation state on neutrophils in vivo, and that rTEM neutrophils are aligned with remote organ damage. Thus, exploiting recent technological advancements and capabilities, the current proposal aims to gain an in-depth understanding of the prevalence, molecular signature and pathogenic role of this “subset” of neutrophils, most notably in ageing. Furthermore, hypothesizing that the activation state of rTEM neutrophils maybe beneficial for the host, the project will for the first time explore the potential protective, and thus physiological, role of rTEM neutrophils against pathogens.