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Beyond oxidative stress: an immunologist's guide to reactive oxygen species

Key Points

  • Reactive oxygen species (ROS) include superoxide, hydrogen peroxide, singlet oxygen, ozone, hypohalous acids and organic peroxides. They interact with and share some of the actions of other classes of small, reactive, endogenous signalling molecules — reactive nitrogen species such as NO and NO2; H2S or its anion, HS; and carbon monoxide.

  • ROS can both promote and prevent cell death, cancer, ageing and inflammation. For example, ROS mediate inflammasome activation, but patients with chronic granulomatous disease, who lack a functional form of a principal ROS-producing enzyme, NADPH oxidase 2 (NOX2), demonstrate considerable susceptibility to infection, as well as non-resolving inflammation.

  • The numerous enzymatic sources of ROS include mitochondria and multiple isoforms of NOXs. The first NOX, now called NOX2, was discovered in neutrophils, but NOXs contribute to signal transduction in diverse cell types. ROS are produced following B and T cell receptor stimulation and can dictate whether T cell activation is fostered or impeded.

  • Many antioxidant systems contribute to the regulation of ROS, including superoxide dismutases, catalases and the enzymes of the glutathione redox cycle, which reflects the widespread functional effects of ROS.

  • Reactions involving ROS demonstrate atomic rather than molecular specificity. That is, ROS preferentially react with certain types of atoms and most readily with a subset of those atoms, but the atomic targets of ROS are distributed in many different macromolecules. For example, ROS preferentially react with the sulphur atom in some but not other cysteine residues; the cysteine thiols that are most susceptible include many that participate in enzyme active sites, such as in phosphatases. This kind of specificity equips ROS to influence many different signalling pathways simultaneously.

  • The immunosuppressive capacity of myeloid-derived suppressor cells and regulatory T cells results in part from their production of ROS. Tumour cells also produce ROS, which can contribute to their immunosuppressive and metastatic potential.

Abstract

Reactive oxygen species (ROS) react preferentially with certain atoms to modulate functions ranging from cell homeostasis to cell death. Molecular actions include both inhibition and activation of proteins, mutagenesis of DNA and activation of gene transcription. Cellular actions include promotion or suppression of inflammation, immunity and carcinogenesis. ROS help the host to compete against microorganisms and are also involved in intermicrobial competition. ROS chemistry and their pleiotropy make them difficult to localize, to quantify and to manipulate — challenges we must overcome to translate ROS biology into medical advances.

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Figure 1: The broad range of ROS signalling is influenced by ROS production and catabolism, and by cellular adaptation.
Figure 2: ROS and their atomic specificity.
Figure 3: Examples of transcriptional regulation by ROS acting at the plasma membrane or in the cytosol.
Figure 4: Regulation of HIF1α by mitochondrial ROS production during hypoxia.
Figure 5: Regulation of transcription through DNA targeting by intranuclear ROS.

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Acknowledgements

A.C.-B. is a member of the Weill Cornell/Rockefeller/Sloan-Kettering Tri-Institutional MD-PhD Programme, which is supported by the Medical Scientist Training Program grant (GM07739) from the National Instiute of General Medical Sciences, USA. The Department of Microbiology and Immunology is supported by the William Randolph Hearst Trust.

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Glossary

Iron–sulphur clusters

Prosthetic groups that are required for the function of some enzymes. In iron–sulphur clusters two, three or four atoms of iron are attached to the protein through two or four sulphydryl groups.

Uncoupling proteins

Proteins in the mitochondrial inner membrane that can divert the proton gradient away from the formation of ATP, resulting in the generation of heat instead.

Xenobiotics

Small chemical compounds that enter an organism unnaturally, such as drugs or pollutants.

Acidic dissociation constant

(pKa). The equilibrium constant for the dissociation of an acid into its conjugate base and hydrogen ion, expressed as the negative logarithm. The lower the pKa of a sulphydryl group, the greater the likelihood that the sulphur will be anionic at ambient pH.

Chronic granulomatous disease

(CGD). An immunodeficiency state manifested by recurrent, often life-threatening, infections and the excessive formation of granulomas, caused by mutations in any one of four subunits of NADP oxidase 2.

Granulomas

Histological collections of macrophages, usually surrounded by lymphocytes and sometimes fibrocytes. Some of the macrophages might seem to be 'epithelioid' or fuse to become multinucleated giant cells. Granuloma formation is a chronic inflammatory response to various infectious and non-infectious agents.

Neddylation

A process that is analogous to ubiquitylation, in which ubiquitin-like protein NEDD8 is conjugated to a protein substrate.

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Nathan, C., Cunningham-Bussel, A. Beyond oxidative stress: an immunologist's guide to reactive oxygen species. Nat Rev Immunol 13, 349–361 (2013). https://doi.org/10.1038/nri3423

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