Neutrophil heterogeneity and fate in inflamed tissues: implications for the resolution of inflammation

Abstract

Neutrophils are polymorphonuclear leukocytes that play a central role in host defense against infection and tissue injury. They are rapidly recruited to the inflamed site and execute a variety of functions to clear invading pathogens and damaged cells. However, many of their defense mechanisms are capable of inflicting collateral tissue damage. Neutrophil-driven inflammation is a unifying mechanism underlying many common diseases. Efficient removal of neutrophils from inflammatory loci is critical for timely resolution of inflammation and return to homeostasis. Accumulating evidence challenges the classical view that neutrophils represent a homogeneous population and that halting neutrophil influx is sufficient to explain their rapid decline within inflamed loci during the resolution of protective inflammation. Hence, understanding the mechanisms that govern neutrophil functions and their removal from the inflammatory locus is critical for minimizing damage to the surrounding tissue and for return to homeostasis. In this review, we briefly address recent advances in characterizing neutrophil phenotypic and functional heterogeneity and the molecular mechanisms that determine the fate of neutrophils within inflammatory loci and the outcome of the inflammatory response. We also discuss how these mechanisms may be harnessed as potential therapeutic targets to facilitate resolution of inflammation.

β2 Integrin Regulation of Neutrophil Functional Plasticity and Fate in the Resolution of Inflammation

“…Rapid recruitment of neutrophils into infected or injured tissues is critical for the elimination of invading microorganisms and tissue repair (1). Ideally, once the pathogens are cleared, cessation of neutrophil recruitment and removal of emigrated neutrophils from the inflamed site will assure timely resolution of inflammation and return to homeostasis (2)(3)(4). Aberrant neutrophil Abbreviations: AG, azurophilic granule; C5aR, complement 5a receptor; CG, cathepsin G; EC, endothelial cell; JAM-C, junctional adhesion molecule-C; MF, macrophage; MPO, myeloperoxidase; NE, neutrophil elastase; NET, neutrophil extracellular traps; PICD, phagocytosis-induced cell death; PR3, proteinase 3; TEM, transendothelial migration.…”

Identification of SARS-CoV-2-specific immune alterations in acutely ill patients

“…Diapedesis of circulating leukocytes is a crucial inflammatory step in immune responses that, when out of control, can cause serious collateral damage (40, 41). To determine whether COVID-19 affects the trafficking potential of circulating leukocytes, we assessed a selection of key trafficking molecules (ICAM-1, ALCAM, CCR2, CD11c) on the different immune cell populations.…”

Sterile Inflammation Alters Neutrophil Kinetics in Mice

“…In this context, a recent study by Ballesteros et al(6) shows that neutrophil half-life in different tissues under steady-state conditions is similar (except in skin) to their half-life in the blood. It has also been suggested that inflammation may extend neutrophils’ lifespan at the inflammatory tissue site(2, 41, 42). Our data show an increase in half-life (and consequently lifespan) of neutrophils at a sterile inflammatory site if the inflammation induces EG-like conditions.…”