Damage-associated molecular patterns control neutrophil recruitment

Abstract

Neutrophils are recruited to a site of infection or injury where they help initiate the acute inflammatory response. In instances of sterile inflammation, where no microbial threats are present, this neutrophil recruitment is mediated by the release of danger signals or damage-associated molecular patterns (DAMPs) from disrupted cells and tissues. At basal state, many of these substances are sequestered and remain hidden within the cell, but are released following the rupture of the plasma membrane. In other instances, these DAMPs are undetected by the innate immune system unless chemically or proteolytically modified by tissue damage. DAMPs may be directly detected by neutrophils themselves and modulate their recruitment to sites of damage or, alternatively, they can act on other cell types which in turn facilitate the arrival of neutrophils to a site of injury. In this review, we outline the direct and indirect effects of a number of DAMPs, notably extracellular ATP, mitochondrial formylated peptides and mitochondrial DNA, all of which are released by necrotic cells. We examine the effect of these substances on the recruitment and behaviour of neutrophils to sites of sterile injury. We also highlight research which suggests that neutrophils are actively involved in triggering the resolution phase of an inflammatory response. This review brings to light a growing body of work that demonstrates that the release of DAMPs and the ensuing influx of neutrophils plays an important functional role in the inflammatory response, even when no pathogens are present.

Fig. 1

Sterile injury causes rupture of the plasma membrane and disruption of mitochondria. This releases ATP from damaged cells, and formylated peptides (which are normally sequestered within the mitochondria) and mtDNA. ATP, once released, activates the NLRP3 inflammasome in nearby sentinel immune cells such as macrophages (Mφ), generating functional IL-1β. Detection of this cytokine and of mtDNA by endothelial cells causes the upregulation of adhesion molecules on their lumenal surface and the production of chemokine gradients. Neutrophils are subsequently recruited from the vasculature to the general area of insult. There, they are guided to the site of tissue necrosis by dominant formyl peptide receptor signals, which not only direct migration, but also block signalling induced by distracting gradients of intermediate chemokines.