Neutrophil clearance: when the party is over, clean-up begins

Abstract

Maintenance of circulating, functional neutrophils and their robust recruitment to tissues in response to injury and/or microbial infection are crucial for host defense. Equally important, although less well understood, are the processes for removal of these short-lived cells. Here, we review recent findings of novel neutrophil characteristics that determine removal. These neutrophil-derived signals, in turn, can shape the responses of other cells and surrounding tissues and promote a return to homeostasis. If not removed, dying neutrophils disintegrate and release phlogistic cargo that can further contribute to ongoing inflammation, tissue destruction, or autoimmunity.

Fig. 1. Time course of tissue neutrophilia in acute inflammation

a). Following tissue injury or infection (e.g. zymosan-induced peritonitis), neutrophils (N) are simultaneously recruited to the site and removed in situ by macrophages (M). Neutrophilia often resolves dramatically with accumulation of few apoptotic neutrophils supporting mechanisms for efficient, high-capacity clearance. b) Time course of efferocytosis by macrophages in peritonitis.

Fig. 2. Possible death pathways for neutrophils and impact on resolution or perpetuation of inflammation

Recruited neutrophils succumb to various death pathways within tissues (blue boxes). Based on signaling for their recognition by macrophages, and the stage at which they are removed, inflammatory consequences will vary across a continuum from anti-inflammatory and immunosuppressive to pro-inflammatory and immunogenic.

Fig. 3. Signaling for efferocytosis

An apoptotic cell presents signals on its surface or recruits bridge molecules from the milieu that serve as “eat me” signals to macrophages. “Eat me” signals both tether the apoptotic cell to the macrophage and “tickle” or signal for it to reorganize its cytoskeleton for uptake. Uptake is opposed by “don’t eat me” signals usually cleared from the cell or segregated from “eat me” signals as the neutrophil undergoes apoptosis. Other factors serve as enhancers to improve efficiency of uptake, or as inhibitors to suppress uptake. Figure published with permission of the Journal of Leukocyte Biology.