Pathway Human Homo sapiens

ROS and RNS production in phagocytes

R-HSA-1222556 in Reactome release 97: under Innate Immune System, with 36 genes placed in it by the mapping files and 1 child pathway in the hierarchy.

The same number in the other species

Reactome writes the mouse and rat events it infers from a human pathway under the human number with the species token. A door opens only where that species' own list in this release holds the id: R-MMU-1222556 (mouse), R-RNO-1222556 (rat). Whether the event was inferred from this one is what the record says.

The record
The genes
Parents and children

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This page reads the pathway's record from its source while you read the rest; with scripts off the card stays at its loading line. Reload with scripts on to see it, or open the source's own page from the link in the card.

01The record

Reactome's own record of this pathway

What this tells you

The pathway list, the hierarchy and the genes on this page are read from the files Reactome publishes for Reactome release 97, built into this site on 2026-09-09: the pathway list, the hierarchy relationship file and the two gene mapping files. The record card is the one live read, Reactome's own record of this pathway.

Reactome's download page describes the mapping files: Mapping files link the source database identifier to the lowest level pathway diagram or subset of the pathway, all levels of the pathway hierarchy or database identifier to all reactions. [R13] The gene list here is the all-levels mapping of NCBI Gene ids, filled from the all-levels mapping of Ensembl ids where the NCBI file has no row for a gene; each row names which file it came from by the shape of its source id. Each row carries the evidence codes the file writes for it, as written and unranked, and both where the file writes both; no page of Reactome's documentation the survey read defines the codes, so this page does not expand them. A gene id the identity files do not name is kept as the source's own id with no door rather than turned into a symbol.

On citing what a search finds, Reactome says: It should be remembered that while we strive to contain the most current and accurate data, Reactome should not be used in citations where other primary sources of information are available. [R12] The record card prints the literature Reactome attaches to a curated pathway for that reason. The data are public domain: All data in the Reactome database and files derived from that data are licensed under the Creative Commons Public Domain Dedication (CC0). User may copy, modify, and distribute these data, even for commercial purposes, without asking for permission. Attribution is encouraged but not required. [R10] The pathway illustrations are licensed apart, under CC BY 4.0, and none is shown here.

A gene on this list is one Reactome places in this pathway in this release, and that is all the row says: it does not say the gene is expressed in a tissue or associated with a disease, which are the other two explorers' questions, read from other sources. Reactome's papers of record are [R01] [R02].

[R01] Ragueneau E, Gong C, Sinquin P, Sevilla C, Beavers D, Grentner A, et al. (2026). The Reactome Knowledgebase 2026. Nucleic Acids Research 54:D673-D681. PMID 41251150, doi 10.1093/nar/gkaf1223.
[R02] Milacic M, Beavers D, Conley P, Gong C, Gillespie M, Griss J, et al. (2024). The Reactome Pathway Knowledgebase 2024. Nucleic Acids Research 52:D672-D678. PMID 37941124, doi 10.1093/nar/gkad1025.
[R10] Reactome, reactome.org. License Agreement. https://reactome.org/license, read 2026-09-09.
[R12] Reactome, reactome.org. Citing us. https://reactome.org/cite, read 2026-09-09.
[R13] Reactome, reactome.org. Download. https://reactome.org/download-data, read 2026-09-09.

Stable id: R-HSA-1222556.11
Class: Pathway
Species: Homo sapiens (human)
Inferred: no: a curated human pathway
Disease pathway: no
Released: 2012-06-12
Last updated: 2019-09-09
Events inside: 32, counted from the record

The first line of defense against infectious agents involves an active recruitment of phagocytes to the site of infection. Recruited cells include polymorhonuclear (PMN) leukocytes (i.e., neutrophils) and monocytes/macrophages, which function together as innate immunity sentinels (Underhill DM & Ozinsky A 2002; Stuart LM & Ezekowitz RA 2005; Flannagan RS et al. 2012). Dendritic cells are also present, serving as important players in antigen presentation for ensuing adaptive responses (Savina A & Amigorena S 2007). These cell types are able to bind and engulf invading microbes into a membrane-enclosed vacuole - the phagosome, in a process termed phagocytosis. Phagocytosis can be defined as the receptor-mediated engulfment of particles greater than 0.5 micron in diameter. It is initiated by the cross-linking of host cell membrane receptors following engagement with their cognate ligands on the target surface (Underhill DM & Ozinsky A 2002; Stuart LM & Ezekowitz RA 2005; Flannagan RS et al. 2012). When engulfed by phagocytes, microorganisms are exposed to a number of host defense microbicidal events within the resulting phagosome. These include the production of reactive oxygen and nitrogen species (ROS and RNS, RONS) by specialized enzymes (Fang FC et al. 2004; Kohchi C et al. 2009; Gostner JM et al. 2013; Vatansever F et al. 2013). NADPH oxidase (NOX) complex consume oxygen to produce superoxide radical anion (O2.-) and hydrogen peroxide (H2O2) (Robinson et al. 2004). Induced NO synthase (iNOS) is involved in the production of NO, which is the primary source of all RNS in biological systems (Evans TG et al. 1996). The phagocyte NADPH oxidase and iNOS are expressed in both PMN and mononuclear phagocytes and both cell types have the capacity for phagosomal burst activity. However, the magnitude of ROS generation in neutrophils far exceeds that observed in macrophages (VanderVen BC et al. 2009). Macrophages are thought to produce considerably more RNS than neutrophils (Fang FC et al. 2004; Nathan & Shiloh 2000).

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).

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).

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.

Literature Reactome attaches

Antimicrobial mechanisms of phagocytes and bacterial evasion strategiesNat Rev Microbiol, 2009, vol. 7, p. 355-66PubMed 19369951
Reactive oxygen species in the immune systemInt. Rev. Immunol., 2013, vol. 32, p. 249-70PubMed 23617726

Reactome's record lists 14 orthologous events, R-RNO-1222556 (Rattus norvegicus), R-MMU-1222556 (Mus musculus) among the species this site serves, and 12 in species this site opens no page for.

Reactome ContentService, this pathway's record · Reactome v97 · read 2026-10-01 ET · Reactome pathway browser"ROS and RNS production in phagocytes". Reactome, release 97, https://reactome.org/PathwayBrowser/#/R-HSA-1222556 with StableID: R-HSA-1222556.11 (accessed 2026-10-01 ET). Reactome version 97 (CC0).

Reading this pathway's record from Reactome (the pathway record).Still reading. A first read of a pathway can take a while; this page waits up to 35 seconds for it, and its scripts then bring in the panel, or a line saying what did not arrive.

02The genes

Genes Reactome places in this human pathway

The mapping files place 36 genes in this human pathway; showing 1 to 36, in pages of 100, sorted by symbol for reading. The order carries no ranking.

Genes Reactome places in this human pathway, page 1 of 1
Gene	Authority id	Mapping file id	Evidence codes
GeneATP6V0A1	AuthorityHGNC:865	Mapping file id535 NCBI file	EvidenceTAS
GeneATP6V0A2	AuthorityHGNC:18481	Mapping file id23545 NCBI file	EvidenceTAS
GeneATP6V0A4	AuthorityHGNC:866	Mapping file id50617 NCBI file	EvidenceTAS
GeneATP6V0B	AuthorityHGNC:861	Mapping file id533 NCBI file	EvidenceTAS
GeneATP6V0C	AuthorityHGNC:855	Mapping file id527 NCBI file	EvidenceTAS
GeneATP6V0D1	AuthorityHGNC:13724	Mapping file id9114 NCBI file	EvidenceTAS
GeneATP6V0D2	AuthorityHGNC:18266	Mapping file id245972 NCBI file	EvidenceTAS
GeneATP6V0E1	AuthorityHGNC:863	Mapping file id8992 NCBI file	EvidenceTAS
GeneATP6V0E2	AuthorityHGNC:21723	Mapping file id155066 NCBI file	EvidenceTAS
GeneATP6V1A	AuthorityHGNC:851	Mapping file id523 NCBI file	EvidenceTAS
GeneATP6V1B1	AuthorityHGNC:853	Mapping file id525 NCBI file	EvidenceTAS
GeneATP6V1B2	AuthorityHGNC:854	Mapping file id526 NCBI file	EvidenceTAS
GeneATP6V1C1	AuthorityHGNC:856	Mapping file id528 NCBI file	EvidenceTAS
GeneATP6V1C2	AuthorityHGNC:18264	Mapping file id245973 NCBI file	EvidenceTAS
GeneATP6V1D	AuthorityHGNC:13527	Mapping file id51382 NCBI file	EvidenceTAS
GeneATP6V1E1	AuthorityHGNC:857	Mapping file id529 NCBI file	EvidenceTAS
GeneATP6V1E2	AuthorityHGNC:18125	Mapping file id90423 NCBI file	EvidenceTAS
GeneATP6V1F	AuthorityHGNC:16832	Mapping file id9296 NCBI file	EvidenceTAS
GeneATP6V1G1	AuthorityHGNC:864	Mapping file id9550 NCBI file	EvidenceTAS
GeneATP6V1G2	AuthorityHGNC:862	Mapping file id534 NCBI file	EvidenceTAS
GeneATP6V1G3	AuthorityHGNC:18265	Mapping file id127124 NCBI file	EvidenceTAS
GeneATP6V1H	AuthorityHGNC:18303	Mapping file id51606 NCBI file	EvidenceTAS
GeneCYBA	AuthorityHGNC:2577	Mapping file id1535 NCBI file	EvidenceTAS
GeneCYBB	AuthorityHGNC:2578	Mapping file id1536 NCBI file	EvidenceTAS
GeneHVCN1	AuthorityHGNC:28240	Mapping file id84329 NCBI file	EvidenceTAS
GeneLPO	AuthorityHGNC:6678	Mapping file id4025 NCBI file	EvidenceTAS
GeneMPO	AuthorityHGNC:7218	Mapping file id4353 NCBI file	EvidenceTAS
GeneNCF1	AuthorityHGNC:7660	Mapping file id653361 NCBI file	EvidenceTAS
GeneNCF2	AuthorityHGNC:7661	Mapping file id4688 NCBI file	EvidenceTAS
GeneNCF4	AuthorityHGNC:7662	Mapping file id4689 NCBI file	EvidenceTAS
GeneNOS1	AuthorityHGNC:7872	Mapping file id4842 NCBI file	EvidenceTAS
GeneNOS2	AuthorityHGNC:7873	Mapping file id4843 NCBI file	EvidenceTAS
GeneNOS3	AuthorityHGNC:7876	Mapping file id4846 NCBI file	EvidenceTAS
GeneRAC2	AuthorityHGNC:9802	Mapping file id5880 NCBI file	EvidenceTAS
GeneSLC11A1	AuthorityHGNC:10907	Mapping file id6556 NCBI file	EvidenceTAS
GeneTCIRG1	AuthorityHGNC:11647	Mapping file id10312 NCBI file	EvidenceTAS

Evidence codes on this page: TAS, as the mapping file writes them; a row carrying two was written twice by the file, once under each. The mapping file id says which file placed the gene: an NCBI Gene id from NCBI2Reactome_All_Levels.txt, an Ensembl gene id from Ensembl2Reactome_All_Levels.txt. The two files can disagree about a code, so a row's codes are the one file's view. Measured by this site's build over this release on 2026-09-09: of the 138,908 human pathway-gene pairs both files place, 207 (0.149 per cent, over 47 genes) carry TAS in the Ensembl file where the NCBI rows carry IEA alone.

Reactome mapping files, the human rows for this pathway · Reactome release 97 · read 2026-09-09 · Reactome downloads"NCBI2Reactome_All_Levels.txt" and "Ensembl2Reactome_All_Levels.txt", Reactome, release 97, https://reactome.org/download-data/ (date of access 2026-09-09). Data CC0; attribution encouraged.

03The hierarchy

Parents and children in this release's hierarchy

Parents

Innate Immune SystemR-HSA-1682491,207 genes

Children

Events associated with phagocytolytic activity of PMN cellsR-HSA-89414132 genes

Reactome's hierarchy is a graph rather than a tree: a pathway can sit under more than one parent, and the gene counts are each pathway's own placements at every level under it, so a parent's count is not the sum of its children's.

Reactome, the human pathway list and hierarchy relationship file · Reactome release 97 · read 2026-09-09 · Reactome downloads"ReactomePathways.txt" and "ReactomePathwaysRelation.txt", Reactome, release 97, https://reactome.org/download-data/ (date of access 2026-09-09). Data CC0; attribution encouraged.