ROS and RNS production in phagocytes (Homo sapiens)
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The presence of RONS characterized by a relatively low reactivity, such as H2O2, O2˙− or NO, has no deleterious effect on biological environment (Attia SM 2010; Weidinger A & and Kozlov AV 2015). Their activity is controlled by endogenous antioxidants (both enzymatic and non-enzymatic) that are induced by oxidative stress. However the relatively low reactive species can initiate a cascade of reactions to generate more damaging “secondary� species such as hydroxyl radical (•OH), singlet oxygen or peroxinitrite (Robinson JM 2008; Fang FC et al. 2004). These "secondary" RONS are extremely toxic causing irreversible damage to all classes of biomolecules (Weidinger A & and Kozlov AV 2015; Fang FC et al. 2004; Kohchi C et al. 2009; Gostner JM et al. 2013; Vatansever F et al. 2013).<p>Although macrophages and neutrophils use similar mechanisms for the internalization of targets, there are differences in how they perform phagocytosis and in the final outcome of the process (Tapper H & Grinstein S 1997; Vierira OV et al. 2002). Once formed, the phagosome undergoes an extensive maturation process whereby it develops into a microbicidal organelle able to eliminate the invading pathogen. Maturation involves re-modeling both the membrane of the phagosome and its luminal contents (Vierira OV et al. 2002). In macrophages, phagosome formation and maturation follows a series of strictly coordinated membrane fission/fusion events between the phagosome and compartments of the endo/lysosomal network gradually transforming the nascent phagosome into a phagolysosome, a degradative organelle endowed with potent microbicidal properties (Zimmerli S et al. 1996; Vierira OV et al. 2002). Neutrophils instead contain a large number of preformed granules such as azurophilic and specific granules that can rapidly fuse with phagosomes delivering antimicrobial substances (Karlsson A & Dahlgren C 2002; Naucler C et al. 2002; Nordenfelt P and Tapper H 2011). Phagosomal pH dynamics may also contribute to the maturation process by regulating membrane traffic events. The microbicidal activity of macrophages is characterized by progressive acidification of the lumen (down to pH 4–5) by the proton pumping vATPase. A low pH is a prerequisite for optimal enzymatic activity of most late endosomal/lysosomal hydrolases reported in macrophages. Neutrophil phagosome pH regulation differs significantly from what is observed in macrophages (Nordenfelt P and Tapper H 2011; Winterbourn CC et al. 2016). The massive activation of the oxidative burst is thought to result in early alkalization of neutrophil phagosomes which is linked to proton consumption during the generation of hydrogen peroxide (Segal AW et al. 1981; Levine AP et al. 2015). Other studies showed that neutrophil phagosome maintained neutral pH values before the pH gradually decreased (Jankowski A et al. 2002). Neutrophil phagosomes also exhibited a high proton leak, which was initiated upon activation of the NADPH oxidase, and this activation counteracted phagosomal acidification (Jankowski A et al. 2002).<p>The Reactome module describes ROS and RNS production by phagocytic cells. The module includes cell-type specific events, for example, myeloperoxidase (MPO)-mediated production of hypochlorous acid in neutrophils. It also highlights differences between phagosomal pH dynamics in neutrophils and macrophages. The module describes microbicidal activity of selective RONS such as hydroxyl radical or peroxynitrite. However, detection of any of these species in the phagosomal environment is subject to many uncertainties (Nüsse O 2011; Erard M et al. 2018). The mechanisms by which reactive oxygen/nitrogen species kill pathogens in phagocytic immune cells are still not fully understood. View original pathway at Reactome.</div>
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transported by
NRAMP1transported by
NRAMP1with phagocytolytic activity of PMN
cellsThe superoxide dismutates to hydrogen peroxide, which is used by myeloperoxidase (MPO) to generate other oxidants, including the highly microbicidal species such as hypochlorous acid (Winterbourn CC et al. 2013, 2016).
Other responses of
Mtb to phagocytosisNOX2 complex consists of CYBB (NOX2), CYBA (p22phox), NCF1 (p47phox), NCF2 (p67phox) and NCF4 (p40ohox). RAC1:GTP binds NOX2 complex in response to VEGF signaling by directly interracting with CYBB and NCF2, leading to enhancement of VEGF-signaling through VEGF receptor VEGFR2, which plays a role in angiogenesis (Ushio-Fukai et al. 2002, Bedard and Krause 2007). RAC2:GTP can also activate the NOX2 complex by binding to CYBB and NCF2, leading to production of superoxide in phagosomes of neutrophils which is necessary fo the microbicidal activity of neutrophils (Knaus et al. 1991, Roberts et al. 1999, Kim and Dinauer 2001, Jyoti et al. 2014).
NOX1 complex (composed of NOX1, NOXA1, NOXO1 and CYBA) and NOX3 complex (composed of NOX3, CYBA, NCF1 amd NCF2 or NOXA1) can also be activated by binding to RAC1:GTP to produce superoxide (Cheng et al. 2006, Miyano et al. 2006, Ueyama et al. 2006).
Annotated Interactions
transported by
NRAMP1transported by
NRAMP1The human gene SLC11A1 encodes NRAMP1 (Kishi F, 2004; Kishi F and Nobumoto M, 1995) which can utilize the protonmotive force to mediate divalent iron (Fe2+), zinc (Zn2+) and manganese (Mn2+) influx to or efflux from phagosomes.
The crucial function of voltage gated proton channels in compensating the electrogenic activity of NADPH oxidase during phagocytosis was demonstrated in human phagocytes (DeCoursey TE et al. 2000; Morgan D et al. 2009; Petheo GL et al. 2010; Kovacs I et al. 2014; Henderson LM et al. 1987, 1988). Hv1 knockout (KO) mice have been shown to lack detectable proton current in bone marrow or peripheral blood phagocytic cells (Morgan D et al. 2009; Ramsey IS et al. 2009; El Chemaly A et al. 2010; Capasso M et al. 2010). Furthermore, VSOP/Hv1-/- mouse cells had a more acidic cytosol, were more depolarized, and produced less superoxide and hydrogen peroxide than neutrophils from wild-type mice (Morgan D et al. 2009; El Chemaly A et al. 2010).
HV1 channels differentially regulate the phagosomal pH in neutrophils and macrophages. In macrophages, HV1 channels contributed to rapid phagosomal acidification together with V-ATPases, proton transporters, that are delivered to nascent phagosomes to generate a transmembrane pH gradient of >4 (El Chemaly A et al, 2014). In contrast, HV1 channels maintained a higher pH by sustaining high-level ROS production that is thought to inhibit V-ATPase accumulation on phagosomes in neutrophils (Jankowski A et al. 2002). In a 2015 study using a probe that is more sensitive at higher pH, an average pH closer to 9 was measured in individual phagosomes in neutrophils (Levine AP et al. 2015). The early alkalization of neutrophil phagosomes was also linked to proton consumption during the generation of hydrogen peroxide (Segal AW et al. 1981; Levine AP et al. 2015). Neutrophil phagosomes also exhibited a high proton leak, which was initiated upon activation of the NADPH oxidase, and this activation counteracted phagosomal acidification (Jankowski A et al. 2002).
Membranes are formed by amphiphilic lipids which in most cases studied are glycerophospholipids, composed of two fatty acids, a glycerol moiety, a phosphate group and a variable head group. Bacterial membranes present a large diversity of amphiphilic lipids, including phosphatidylglycerol, phosphatidylethanolamine, cardiolipin and the less frequent phospholipids such as phosphatidylcholine and phosphatidylinositol. Bacteria can also form phosphorus-free membrane lipids such as ornithine lipids, sulfolipids, diacylglyceryl-N,N,N-trimethylhomoserine, glycolipids, diacylglycerol, hopanoids and others. Commonly, the hydrophobic moieties of amphiphilic membrane lipids are formed by linear fatty acids that can be saturated or unsaturated (containing often one and rarely two or more double bonds). (OH.)-dependent abstraction of a hydrogen atom from an unsaturated fatty acid initiates the process of lipid peroxidation by generating a lipid radical, which rapidly adds oxygen to form a lipid peroxyl radical LOO. (not shown here). The peroxyl radicals in turn can further react with lipid molecules to continue the chain reaction, producing lipid hydroperoxides (LOOH), that can break down to more radical species
Defects in NADPH oxidase components are associated with chronic granulomatous disease (CGD) (de Oliveira-Junior EB et al. 2011). Phagocytic cells of CGD patients are unable to produce superoxide ion, and their efficiency in bacterial killing is significantly impaired (Johnston RB Jr et al. 1975; de Oliveira-Junior EB et al. 2011). In addition, macrophages from CGD patients exhibit abnormal function because these cells release higher levels of anti-inflammatory cytokines and lower levels of proinflammatory cytokines in response to bacterial stimuli (Rahman FZ et al. 2009).
Hydroxyl radical reacts with both the basepairs of DNA and the sugar moiety in the oligonucleotides (Dedon PC 2008; Cadet J & Wagner JR 2014). •OH reacts with 2'-deoxyribose in DNA by H abstraction from all its carbons leading to five C-centered radicals (Dedon PC 2008; Cadet J & Wagner JR 2013). The abstraction at C1' gives 2-deoxyribonolactone, the abstraction at C5′ gives 3′-phosphoglycoaldehyde, and abstraction at C4′ gives an intermediate unsaturated dialdehyde that can couple with cytosine to form a DNA inter- or intrastrand cross-link (Dedon PC 2008; Sczepanski JT et al. 2011; Cadet J & Wagner JR 2013). In addition, the C5′-centered radicals of 2-deoxyribose can react with the purine ring in the same nucleoside to produce 8,5'-cyclo-2′-deoxyguanosine (8,5'-cyclo-dGuo) or 8,5'-cyclo-2′-deoxyadenosine (8,5'-cyclo-dAdo), which are among the major lesions in DNA that are formed by attack of hydroxyl radical (Jaruga P et al. 2002; Chatgilialoglu C et al. 2011).
Under normal physiological conditions, when the rates of nitric oxide (NO) production are low, NO can interact directly with biological molecules. Generally, these types of reactions may serve protective regulatory and/or anti-inflammatory functions (Hummel SG et al. 2006; Wink DA et al. 2001). High NO fluxes under pathological conditions enable formation of NO-derived reactive intermediates. The most prevalent NO-derived reactive species produced in vivo are dinitrogen trioxide (N2O3) and peroxynitrite (ONOO-), both of which can mediate additional nitrosative and/or oxidative reactions (Grisham MB et al. 1999; Wink DA & Mitchell JB 1998; Ali AA et al. 2013). N2O3 production requires oxidation of NO first to NO2 which will then combine with NO to form N2O3. Although this reaction is very slow at physiological levels of nitric oxide, it has been suggested that hydrophobic environments, such as those found in the cellular membrane, can accelerate this reaction (Liu X et al. 1997; Moller MN et al. 2007). N2O3 formation regulates the function of many target proteins through the coupling of a nitroso moiety (NO+) to a reactive sulfhydryl group on cysteine, ultimately leading to the formation of RSNO, a process commonly known as S-nitrosylation (Broniowska KA & Hogg N 2012).
Under normal physiological conditions, when the rates of nitric oxide (NO) production are low, NO can interact directly with biological molecules. Generally, these types of reactions may serve protective regulatory and/or anti-inflammatory functions (Hummel SG et al. 2006; Wink DA et al. 2001). High NO fluxes under pathological conditions enable formation of NO-derived reactive intermediates. The most prevalent NO-derived reactive species produced in vivo are dinitrogen trioxide (N2O3) and peroxynitrite (ONOO-), both of which can mediate additional nitrosative and/or oxidative reactions (Grisham MB et al. 1999; Wink DA & Mitchell JB 1998; Ali AA et al. 2013). N2O3 production requires oxidation of NO first to NO2 which will then combine with NO to form N2O3. Although this reaction is very slow at physiological levels of nitric oxide, it has been suggested that hydrophobic environments, such as those found in the cellular membrane, can accelerate this reaction (Liu X et al. 1997; Moller MN et al. 2007). N2O3 formation regulates the function of many target proteins through the coupling of a nitroso moiety (NO+) to a reactive cysteine, ultimately leading to the formation of RSNO, a process commonly known as S-nitrosylation (Broniowska KA & Hogg N 2012).