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Chapter 5 : Reactive Oxygen and Reactive Nitrogen Intermediates in the Immune System
Category: Immunology; Clinical Microbiology
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This chapter reviews the sites of production and the functional diversity of reactive oxygen intermediates (ROIs) and reactive nitrogen intermediates (RNIs) within the immune system with a special emphasis on their host-protective effector and regulator potential. The chapter also deals with the expression and function of Inducible nitric oxide synthase (iNOS). In macrophages, iNOS protein and activity has been detected in three different locations: in the cytosol; in a membranous (particulate) compartment consisting of 50 to 80 nm vesicles; and in the cortical actin cytoskeleton immediately beneath the plasma membrane. The role of ROI and RNI in the immune system is unpleasantly ambiguous: They function as aggressive oxidants that kill microbial intruders and, at the same time, cause collateral damage to host tissues; and they serve as signaling molecules that not only control and tune the immune system, but also alarm the infectious pathogen to switch on mechanisms for protection against the host defense machinery. Therefore, ROI and RNI are potentially beneficial and detrimental at the same time, depending on their concentration, on the tissue microenvironment and the time course of generation, and certainly also on the chemistry of the individual products.
Key Concept Ranking
- Type II Nitric Oxide Synthase
Schematic overview of antimicrobial effector mechanisms of neutrophils and other phagocytes. In resting neutrophils gp91phox (NOX2) and p22phox are located in the plasma membrane (depicted) as well as in the membrane of secondary and tertiary granules (not depicted), all of which can contribute to the formation of phagosomes. Upon stimulation (e.g. exposure to pathogens [black oval], crosslinking of Fcγ-receptors by opsonized particles) the Rho-GTPase Rac (Rac1 or Rac2 depending on the cell-type and species) and p47phox in the cytosol become activated by CARD9-mediated release of GDP-dissociation inhibitor (GDI) and subsequent guanine nucleotide exchange factor (GEF)-mediated exchange of GDP for GTP and by phosphorylation (asteriks), respectively, and translocate to the membrane. Subsequent translocation of p67phox and p40phox leads to the enzymatically active phagocyte NADPH oxidase complex, which generates O2 – on the cell surface or within the phagosome. The O2 – is converted into H2O2, either spontaneously by the acidic pH in phagolysosomes, or by host- or pathogen-derived superoxide dismutases (SOD). The iron-dependent Haber-Weiss-reaction (HWR), catalase (Cat) and myeloperoxidase (MPO) help to generate further species of ROI, all of which contribute to the killing of the pathogens (dashed oval). Inducible nitric oxide synthase (iNOS or NOS2), which is found in the cytosol (not depicted) as well as in a vesicular compartment (nitroxosomes) of macrophages and granulocytes, generates citrulline and nitric oxide (NO) from the amino acid L-arginine and molecular oxygen. Neutrophils contain large numbers of primary, secondary and tertiary granules, which are loaded with a broad spectrum of antimicrobially active compounds (see Table 1 for abbreviations and details).
Generation of nitric oxide from L-arginine by nitric oxide synthases (NOS). Only those cofactors are depicted, which are directly involved in the flux of electrons. The initial product of the reaction is not free ·NO, but a ferric heme-NO complex (not depicted). For further details see text.
Conceptual framework for iNOS-dependent effects in the immune system (for details see text).
Antimicrobial effector mechanisms of phagocytes