Antimicrobial reactive oxygen and nitrogen species: concepts and controversies
TL;DR: A review of the regulation, generation and actions of these molecular mediators, as well as their roles in resisting infection, updates the reader on these concepts and the topical questions in the field.
Abstract: Phagocyte-derived reactive oxygen and nitrogen species are of crucial importance for host resistance to microbial pathogens. Decades of research have provided a detailed understanding of the regulation, generation and actions of these molecular mediators, as well as their roles in resisting infection. However, differences of opinion remain with regard to their host specificity, cell biology, sources and interactions with one another or with myeloperoxidase and granule proteases. More than a century after Metchnikoff first described phagocytosis, and more than four decades after the discovery of the burst of oxygen consumption that is associated with microbial killing, the seemingly elementary question of how phagocytes inhibit, kill and degrade microorganisms remains controversial. This review updates the reader on these concepts and the topical questions in the field.
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TL;DR: This novel ROS-dependent death allows neutrophils to fulfill their antimicrobial function, even beyond their lifespan.
Abstract: Neutrophil extracellular traps (NETs) are extracellular structures composed of chromatin and granule proteins that bind and kill microorganisms. We show that upon stimulation, the nuclei of neutrophils lose their shape, and the eu- and heterochromatin homogenize. Later, the nuclear envelope and the granule membranes disintegrate, allowing the mixing of NET components. Finally, the NETs are released as the cell membrane breaks. This cell death process is distinct from apoptosis and necrosis and depends on the generation of reactive oxygen species (ROS) by NADPH oxidase. Patients with chronic granulomatous disease carry mutations in NADPH oxidase and cannot activate this cell-death pathway or make NETs. This novel ROS-dependent death allows neutrophils to fulfill their antimicrobial function, even beyond their lifespan.
2,481 citations
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...These data further support our fi nding that NADPH oxidase is essential not only for phagosomal killing (Fang, 2004; Segal, 2005) but also for NET formation....
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TL;DR: It is concluded that the MPO system plays an important role in the microbicidal activity of phagocytes and the role of theMPO system in tissue injury.
Abstract: Neutrophilic polymorphonuclear leukocytes (neutrophils) are highly specialized for their primary function, the phagocytosis and destruction of microorganisms. When coated with opsonins (generally complement and/or antibody), microorganisms bind to specific receptors on the surface of the phagocyte and invagination of the cell membrane occurs with the incorporation of the microorganism into an intracellular phagosome. There follows a burst of oxygen consumption, and much, if not all, of the extra oxygen consumed is converted to highly reactive oxygen species. In addition, the cytoplasmic granules discharge their contents into the phagosome, and death of the ingested microorganism soon follows. Among the antimicrobial systems formed in the phagosome is one consisting of myeloperoxidase (MPO), released into the phagosome during the degranulation process, hydrogen peroxide (H2O2), formed by the respiratory burst and a halide, particularly chloride. The initial product of the MPO-H2O2-chloride system is hypochlorous acid, and subsequent formation of chlorine, chloramines, hydroxyl radicals, singlet oxygen, and ozone has been proposed. These same toxic agents can be released to the outside of the cell, where they may attack normal tissue and thus contribute to the pathogenesis of disease. This review will consider the potential sources of H2O2 for the MPO-H2O2-halide system; the toxic products of the MPO system; the evidence for MPO involvement in the microbicidal activity of neutrophils; the involvement of MPO-independent antimicrobial systems; and the role of the MPO system in tissue injury. It is concluded that the MPO system plays an important role in the microbicidal activity of phagocytes.
2,070 citations
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TL;DR: The field of antioxidants and free radicals is often perceived as focusing around the use of antioxidant supplements to prevent human disease, but in fact, antioxidants/free radicals permeate the whole of life, creating the field of redox biology.
Abstract: The field of antioxidants and free radicals is often perceived as focusing around the use of antioxidant supplements to prevent human disease. In fact, antioxidants/free radicals permeate the whole of life, creating the field of redox biology. Free radicals are not all bad, nor antioxidants all good
2,034 citations
Cites background from "Antimicrobial reactive oxygen and n..."
...ROS production in animals by phagocytes and by other cells in the gastrointestinal and respiratory tracts is a defense against microorganisms (Fang, 2004; Donko et al., 2005)....
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...These were originally described in phagocytes (Fang, 2004), but are now known to be widespread in animal (and plant, see the rest of this issue) cells....
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TL;DR: This review examines how target selectivity and antioxidant effectiveness vary for different oxidants and highlights areas where greater understanding is required on the fate of oxidants generated by cellular NADPH oxidases and on the identification of oxidant sensors in cell signaling.
Abstract: There is a vast literature on the generation and effects of reactive oxygen species in biological systems, both in relation to damage they cause and their involvement in cell regulatory and signaling pathways. The biological chemistry of different oxidants is becoming well understood, but it is often unclear how this translates into cellular mechanisms where redox changes have been demonstrated. This review addresses this gap. It examines how target selectivity and antioxidant effectiveness vary for different oxidants. Kinetic considerations of reactivity are used to assess likely targets in cells and how reactions might be influenced by restricted diffusion and compartmentalization. It also highlights areas where greater understanding is required on the fate of oxidants generated by cellular NADPH oxidases and on the identification of oxidant sensors in cell signaling.
2,011 citations
Cites background from "Antimicrobial reactive oxygen and n..."
...Space limitations preclude coverage here, and for information on production of nitric oxide and its antimicrobial and inflammatory actions readers are referred to other review...
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TL;DR: This Review summarizes the current understanding of the microbial nitrogen-cycling network, including novel processes, their underlying biochemical pathways, the involved microorganisms, their environmental importance and industrial applications.
Abstract: Nitrogen is an essential component of all living organisms and the main nutrient limiting life on our planet By far, the largest inventory of freely accessible nitrogen is atmospheric dinitrogen, but most organisms rely on more bioavailable forms of nitrogen, such as ammonium and nitrate, for growth The availability of these substrates depends on diverse nitrogen-transforming reactions that are carried out by complex networks of metabolically versatile microorganisms In this Review, we summarize our current understanding of the microbial nitrogen-cycling network, including novel processes, their underlying biochemical pathways, the involved microorganisms, their environmental importance and industrial applications
1,794 citations
References
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TL;DR: The next ten years will bring forth evidence that NO is produced in slime molds, locusts, beetles, horseshoe crabs, mollusks, chickens, mice, rats, cows, and humans, and its physiologic roles will be at least as protean as those discovered for corticosteroids in the 194Os- 1980s.
2,917 citations
"Antimicrobial reactive oxygen and n..." refers background in this paper
...However, unlike neuronal NOS (nNOS) and endothelial NOS (eNOS), iNOS activity is not controlled by intracellular calcium concentration...
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TL;DR: Reporter constructs containing truncated promoter regions revealed that activation of NF-kappa B/Rel is critical in the induction of iNOS by LPS, however, additional, newly synthesized proteins contribute to the NF- kappa Bd-dependent transcription factor complex on the iN OS promoter in LPS-treated mouse macrophages.
2,195 citations
"Antimicrobial reactive oxygen and n..." refers background in this paper
...together with signalling from proinflammatory cytokines (such as IFNs, IL-1β and TNF-α) triggers signalling cascades that lead to iNOS transcription, including the p38 mitogen-activated protein kinase (MAPK), NF-κB and Janus-activated kinase–signal transducer and activator of transcription–interferon regulatory factor 1 (JAK–STAT–IRF1) pathway...
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TL;DR: This review attempts to present the still-incomplete understanding of how reactive oxygen species are formed inside cells and the mechanisms by which they damage specific target molecules.
Abstract: The phenomenon of oxygen toxicity is universal, but only recently have we begun to understand its basis in molecular terms. Redox enzymes are notoriously nonspecific, transferring electrons to any good acceptor with which they make electronic contact. This poses a problem for aerobic organisms, since molecular oxygen is small enough to penetrate all but the most shielded active sites of redox enzymes. Adventitious electron transfers to oxygen create superoxide and hydrogen peroxide, which are partially reduced species that can oxidize biomolecules with which oxygen itself reacts poorly. This review attempts to present our still-incomplete understanding of how reactive oxygen species are formed inside cells and the mechanisms by which they damage specific target molecules. The vulnerability of cells to oxidation lies at the root of obligate anaerobiosis, spontaneous mutagenesis, and the use of oxidative stress as a biological weapon.
2,023 citations
"Antimicrobial reactive oxygen and n..." refers background in this paper
...The presence of saturated and monounsaturated fatty acids in bacterial membranes probably limits the potential for chain-peroxidation reaction...
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TL;DR: It is proposed that the cell may also decrease such toxicity by diminishing available NAD(P)H and by utilizing oxygen itself to scavenge active free radicals into superoxide, which is then destroyed by superoxide dismutase.
Abstract: A major portion of the toxicity of hydrogen peroxide in Escherichia coli is attributed to DNA damage mediated by a Fenton reaction that generates active forms of hydroxyl radicals from hydrogen peroxide, DNA-bound iron, and a constant source of reducing equivalents. Kinetic peculiarities of DNA damage production by hydrogen peroxide in vivo can be reproduced by including DNA in an in vitro Fenton reaction system in which iron catalyzes the univalent reduction of hydrogen peroxide by the reduced form of nicotinamide adenine dinucleotide (NADH). To minimize the toxicity of oxygen radicals, the cell utilizes scavengers of these radicals and DNA repair enzymes. On the basis of observations with the model system, it is proposed that the cell may also decrease such toxicity by diminishing available NAD(P)H and by utilizing oxygen itself to scavenge active free radicals into superoxide, which is then destroyed by superoxide dismutase.
1,997 citations
"Antimicrobial reactive oxygen and n..." refers background in this paper
...Studies in Escherichia coli have shown that at low concentrations of H 2 O 2 the main mechanism of ROS-dependent antibacterial activity is DNA damag...
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TL;DR: Mice deficient in inducible nitric oxide synthase (iNOS) were generated to test the idea that iNOS defends the host against infectious agents and tumor cells at the risk of contributing to tissue damage and shock, and found there exist both iN OS-dependent and iNos-independent routes to LPS-induced hypotension and death.
1,487 citations