How human neutrophils kill and degrade microbes: an integrated view

Abstract

Neutrophils constitute the dominant cell in the circulation that mediates the earliest innate immune human responses to infection. The morbidity and mortality from infection rise dramatically in patients with quantitative or qualitative neutrophil defects, providing clinical confirmation of the important role of normal neutrophils for human health. Neutrophil-dependent anti-microbial activity against ingested microbes represents the collaboration of multiple agents, including those prefabricated during granulocyte development in the bone marrow and those generated de novo following neutrophil activation. Furthermore, neutrophils cooperate with extracellular agents as well as other immune cells to optimally kill and degrade invading microbes. This brief review focuses attention on two examples of the integrated nature of neutrophil-mediated anti-microbial action within the phagosome. The importance and complexity of myeloperoxidase-mediated events illustrate a collaboration of anti-microbial responses that are endogenous to the neutrophil, whereas the synergy between the phagocyte NADPH (nicotinamide adenine dinucleotide phosphate) oxidase and plasma-derived group IIA phospholipase A(2) exemplifies the collective effects of the neutrophil with an exogenous factor to achieve degradation of ingested staphylococci.

Neutrophil-Epithelial Interactions

“…Detailed reviews of neutrophil killing functions can be found elsewhere. 7 Given this arsenal of destructive power, it is remarkable that recruited neutrophils can efficiently enter tissues and destroy invading pathogens (a process culminating in the resolution of infection/inflammation), usually with little residual tissue damage. In addition, it is well documented that infiltration of inflammatory cells, including neutrophils, macrophages, and lymphocytes, is necessary for the process of mucosal wound healing.…”

Changing world of neutrophils

“…Killing and degradation of the microorganism proceed in the small phagosomal space in a concentrated action of the involved ingredients, although the contribution of the individual factors may vary depending on the type of microorganism [89,91]. The molecular details of these processes have been worked out and summarized in recent excellent reviews [11,58,66,75,77,78,80,102,115].…”

Stable formyl peptide receptor agonists that activate the neutrophil NADPH-oxidase identified through screening of a compound library

“…Accordingly the prototype agonist formylmethionyl-leucyl-phenylalanine (fMLF) is a bacterial produced high-affinity FPR1 agonist that triggers a variety of biologic activities in neutrophils, including chemotaxis, granule secretion, cytokine production, and superoxide release, the latter generated through an activation of an electron transporting NADPH-oxidase [6]. The reactive oxygen species (ROS) derived from the activated NADPH-oxidase are essential for a successful clearance of bacteria during infection as illustrated by the fact that patients lacking a functional oxidase suffer repeatedly from severe bacterial infections [7]. In addition to FPR1, neutrophils express also a closely related receptor, FPR2, that belongs to the same receptor family [4,5].…”