Novel and Converging Ways of NOX2 and SOD3 in Trafficking and Redox Signaling in Macrophages

Abstract

Macrophages and related tissue macrophage populations use the classical NADPH oxidase (NOX2) for the regulated production of superoxide and derived oxidants for pathogen combat and redox signaling. With an emphasis on macrophages, we discuss how sorting into secretory storage vesicles, agonist-responsive membrane trafficking, and segregation into sphingolipid and cholesterol-enriched microdomains (lipid rafts) determine the subcellular distribution and spatial organization of NOX2 and superoxide dismutase-3 (SOD3). We discuss how inflammatory activation of macrophages, in part through small GTPase Rab27A/B regulation of the secretory compartments, mediates the coalescence of these two proteins on the cell surface to deliver a focalized hydrogen peroxide output. In interplay with membrane-embedded oxidant transporters and redox sensitive target proteins, this arrangement allows for the autocrine and paracrine signaling, which govern macrophage activation states and transcriptional programs. By discussing examples of autocrine and paracrine redox signaling, we highlight why formation of spatiotemporal microenvironments where produced superoxide is rapidly converted to hydrogen peroxide and conveyed immediately to reach redox targets in proximal vicinity is required for efficient redox signaling. Finally, we discuss the recent discovery of macrophage-derived exosomes as vehicles of NOX2 holoenzyme export to other cells.

Macrophage Polarization and Reprogramming in Acute Inflammation: A Redox Perspective

“…The superoxide derived from NOX2 can generate H 2 O 2 by spontaneous dismutation, but, more often than not, this dismutation can be mediated by superoxide dismutase 3 (SOD3) in spatially confined microdomains on the cell surface. This coupling confers localized H 2 O 2 production for redox signaling purposes [ 113 ]. Different cytosolic- or membrane-associated proteins can be targets of NOX2/SOD3-derived H 2 O 2 on the macrophage cell surface.…”

Nicotinamide Adenine Dinucleotide Phosphate Oxidases Are Everywhere in Brain Disease, but Not in Huntington’s Disease?

“…NOX2, the classical phagocyte NADPH oxidase, is well known for its bactericidal role in innate immune defense (Nauseef, 2019), but with the advent of the NOX superfamily it was quickly realized that these enzymes occupies an important role as oxidant producers in an intricate network of cellular redox signaling circuits. Hydrogen peroxide is here believed to be the redoxrelevant signaling messenger, and controls the activity of target proteins typically by the reversible oxidation of low pKa cysteines or metal centers (Sies and Jones, 2020;Petersen et al, 2021). The redox targets are diverse, but for the purpose of this review it is worth mentioning that many ion channels, kinases, and phosphatases are regulated or modulated by hydrogen peroxide (Winterbourn, 2013;Sies, 2014;Sies and Jones, 2020).…”

“…For example, in endothelial cells, NOX1 is present in caveolae while NOX4 segregates to focal adhesions (Helmcke et al, 2009); in microglia, NOX1 seems to reside in lysosomes (Cheret et al, 2008), while NOX2 is localized to agonist-responsive secretory vesicles and the plasma membrane (Ejlerskov et al, 2012). Because of the large and polarized shape of neurons it is reasonable to assume that the same can occur in neurons, such that separate redox signaling circuits can function simultaneously in the same cell (see discussion in Petersen et al (2021)). No sorting receptors for NOX have been identified, and there are very few clues to the differential and cell-specific subcellular distribution of the different NOX isoforms, as very few interaction partners of NOX family members have been identified (Park et al, 2004;Ikeda et al, 2005;Gianni et al, 2009).…”

The Catalase KatA Contributes to Microaerophilic H2O2 Priming to Acquire an Improved Oxidative Stress Resistance in Staphylococcus aureus

“…During infections, S. aureus has to cope with reactive oxygen species (ROS), such as superoxide anion (O 2 •− ) and hydrogen peroxide (H 2 O 2 ) [ 4 ], which are produced during the oxidative burst of activated macrophages and neutrophils to kill the invading pathogen [ 5 , 6 , 7 , 8 ]. The NADPH oxidase (NOX2) in the phagosomal membrane catalyses the one-electron transfer to molecular oxygen (O 2 ) to generate O 2 •− , which is dismutated to H 2 O 2 either spontaneously or by superoxide dismutases (SODs), including the extracellular SOD3 [ 6 , 8 , 9 , 10 , 11 ]. Both SOD3 and NOX2 are contained in secretory vesicles in macrophages and neutrophils and the fusion of these vesicles with phagosomes during phagocytosis might provide a mechanism for catalysed H 2 O 2 production [ 11 ].…”

“…The NADPH oxidase (NOX2) in the phagosomal membrane catalyses the one-electron transfer to molecular oxygen (O 2 ) to generate O 2 •− , which is dismutated to H 2 O 2 either spontaneously or by superoxide dismutases (SODs), including the extracellular SOD3 [ 6 , 8 , 9 , 10 , 11 ]. Both SOD3 and NOX2 are contained in secretory vesicles in macrophages and neutrophils and the fusion of these vesicles with phagosomes during phagocytosis might provide a mechanism for catalysed H 2 O 2 production [ 11 ]. However, in neutrophils, the myeloperoxidase MPO is released from azurophilic granula into the phagosomal lumen, catalysing the dismutation of O 2 •− to H 2 O 2 upon infection [ 6 ].…”