The phagocyte respiratory burst: Historical perspectives and recent advances

Abstract

When exposed to certain stimuli, phagocytes (including neutrophils, macrophages and eosinophils) undergo marked changes in the way they handle oxygen. Firstly, their rate of oxygen uptake increases greatly. This is accompanied by (i) the production of large amounts of superoxide and hydrogen peroxide and (ii) the metabolism of large quantities of glucose through the hexose monophosphate shunt. We now know that the oxygen used is not for respiration but for the production of powerful microbiocidal agents downstream of the initial production of superoxide. Concomitantly, glucose is oxidised through the hexose monophosphate shunt to re-generate the NADPH that has been consumed through the reduction of molecular oxygen to generate superoxide. This phagocyte respiratory burst is generated by an NADPH oxidase multi-protein complex that has a catalytic core consisting of membrane-bound gp91phox (CYBB) and p22phox (CYBA) sub-units and cytosolic components p47phox (NCF1), p67phox (NCF2) and p40phox (NCF4). Finally, another cytosolic component, the small G-protein Rac (Rac2 in neutrophils and Rac1 in macrophages) is also required for full activation. The importance of the complex in host defence is underlined by chronic granulomatous disease, a severe life-limiting immunodeficiency caused by mutations in the genes encoding the individual subunits. In this review, I will discuss the experimental evidence that underlies our knowledge of the respiratory burst, outlining how elegant biochemical analysis, coupled with study of patients deficient in the various subunits has helped elucidate the function of this essential part of innate immunity. I will also discuss some exciting recent studies that shed new light on how the abundance of the various components is controlled. Finally, I will explore the emerging role of reactive oxygen species such as superoxide and hydrogen peroxide in the pathogenesis of major human diseases including auto-inflammatory diseases.

Dynamic metabolic reprogramming in dendritic cells: an early response to influenza infection that is essential for effector function

“…R 2 = 0.9101) [46, 47]. However, phagocytes employ radical generation and pH in signaling and innate effector functions, and therefore we used the glycolytic stress test to isolate glycolytic ECAR from lactate and non-glycolytic ECAR as previously described [47–49]. In keeping with our flux analysis, we found that influenza infected DC significantly increased glycolysis resulting in a mean difference of 26.5242 95% CI [1.62, 51.43] (Fig 3A).…”

More Than Just Attractive: How CCL2 Influences Myeloid Cell Behavior Beyond Chemotaxis

“…A hyperactivation of autophagy was observed in human CD11b+ cells upon CCL2 treatment (10). This was shown by detecting an increase in the LC3-II protein (resulting from cleavage off the microtubule-associated protein LC3) that correlates with autophagosome number (199). Together with their other findings of CCL2's influence on cytokine production and macrophage polarization (see CCL2 Induces Context-Specific Macrophage Polarization and Cytokine Secretion), Roca et al suggest that autophagy might play a role in M2 macrophage polarization (10).…”

Where in the world do bacteria experience oxidative stress?

“…3). Its role in suppressing microbial growth is clear, as humans and mice that lack the enzyme are especially vulnerable to infection (Shiloh et al, 1999;Thomas, 2017). However, it has been surprisingly difficult to figure out exactly how phagocytic ROS production suppresses microbial growth (Slauch, 2011).…”