Cell intrinsic functions of neutrophils and their manipulation by pathogens

Abstract

Neutrophils are a crucial first line of defense against infection, migrating rapidly into tissues where they deploy granule components and toxic oxidants for efficient phagocytosis and microbe killing. Subsequent apoptosis and clearance of dying neutrophils are essential for control of infection and resolution of the inflammatory response. A subset of microbial pathogens survive exposure to neutrophils by manipulating phagocytosis, phagosome-granule fusion, oxidant production, and lifespan. Elucidating how they accomplish this unusual feat provides new insights into normal neutrophil function. In this review, we highlight recent discoveries about the ways in which neutrophils use cell-intrinsic mechanisms to control infection, and how these defenses are subverted by pathogens.

Phagocytic killing of microbes by neutrophils. Neutrophils phagocytose microbes that are opsonized with complement (C) and/or antibody (Y) using complement and Fc gamma receptors, respectively (upper right). They also phagocytose microbes that not opsonized (upper left). Fusion with primary (1°) and secondary (2°) granules delivers antimicrobial proteins and peptides (blue and green circles) into the phagosome, or at the phagocytic cup (not shown). See Table for antimicrobial peptides and proteins in these granules. Secondary granule fusion delivers the integral membrane subunits of NADPH oxidase, gp91^phox and p22^phox (flavocytochrome b₅₅₈), to the phagosome. Upon cellular activation, the p40^phox/p47^phox/p67^phox complex is phosphorylated (P) and Rac2 GTPase undergoes GDP → GTP exchange. These cytosolic subunits translocate to the phagosomal membrane and co-assemble with gp91^phox and p22^phox to create the NADPH holoenzyme. Superoxide (O₂●) produced by NADPH oxidase dismutates into hydrogen peroxide (H₂O₂), which is converted into hypochlorous acid (HOCl) by the primary granule enzyme myeloperoxidase (MPO). Fusion with endocytic compartments delivers the vacuolar H+-ATPase to the phagosomal membrane, where it modestly acidifies the phagosome (not shown). Oxidative and non-oxidative components work in concert to kill microbes within the phagosome. As described in the text, certain pathogens avoid intraphagosomal killing by preventing phagocytosis, preventing or redirecting granule fusion with the phagosome, limiting oxidant production, and manipulating neutrophil cell death pathways.