Nitric oxide synthase in innate and adaptive immunity: an update

doi:10.1016/j.it.2015.01.003

Trends in Immunology

Volume 36, Issue 3, March 2015, Pages 161-178

https://doi.org/10.1016/j.it.2015.01.003 Get rights and content

Highlights

•
In addition to its regulation by cytokines, NOS2 is modulated by micromilieu factors.
•
NOS2-derived NO controls pathogens by restricting their access to micronutrients.
•
NOS2 is expressed and functional in specific T cell subsets.
•
NOS2-positive mesenchymal stem cells and lymphatic stromal cells suppress T cells.

Thirty years after the discovery of its production by activated macrophages, our appreciation of the diverse roles of nitric oxide (NO) continues to grow. Recent findings have not only expanded our understanding of the mechanisms controlling the expression of NO synthases (NOS) in innate and adaptive immune cells, but have also revealed new functions and modes of action of NO in the control and escape of infectious pathogens, in T and B cell differentiation, and in tumor defense. I discuss these findings, in the context of a comprehensive overview of the various sources and multiple reaction partners of NO, and of the regulation of NOS2 by micromilieu factors, antisense RNAs, and ‘unexpected’ cytokines.

Section snippets

NO and the immune system: no end (yet) to new paradigms

The production of large amounts of nitrite (NO₂⁻) and nitrate (NO₃⁻) by mouse macrophages stimulated with lipopolysaccharide (LPS) and interferon (IFN)-γ 1, 2, and the L-arginine-dependency of the NO₂⁻ generation and of the tumor cytotoxic activity of activated macrophages 3, 4, were the pioneering observations that ignited the interest of immunologists in the small inorganic radical of nitric oxide (NO). With the subsequent purification and cloning of the enzyme NOS2 5, 6, the production of

Mammalian NO synthases

NOS2 is a homodimeric enzyme that, like all other NOS isoforms, converts L-arginine and oxygen into L-citrulline and NO in a complex oxidoreductase reaction (Box 1 and Figure 1A). A characteristic feature of NOS2 is its lack of expression in strictly resting cells. Instead, it is induced by immunological stimuli in a calcium-independent manner, which led to its original designation as inducible NO synthase (iNOS) [13]. The host cell localization of NOS2 has been mainly investigated in

NO targets and signaling

NO radical, the primary product released from the Fe²⁺–heme complex within NOS2, is a labile compound. Its multiple reaction partners, which explain both the toxic and the regulatory effects of NO, include (i) the thiol groups of cysteines within peptides or proteins, leading to the formation of S-nitrosothiols [55]; (ii) superoxide anions (O₂⁻), which gives rise to peroxynitrous acid/peroxynitrite (ONOO⁻), capable of modifying proteins (e.g., by tyrosine nitration [56]); (iii) divalent cations

Cytokines and microbial products

In the mouse system interferons [IFN-γ and type I IFNs (IFN-α/β)] and microbial pathogens or products (e.g., LPS) are prototypic transcriptional inducers of NOS2 which effectively stimulate macrophages for the release of high amounts of NO. IFNs and LPS elicit the dimerization of STAT1, the expression of interferon-regulatory factor (IRF)-1, and the formation of the interferon-stimulated gamma factor (ISGF) 3-complex (consisting of STAT1, STAT2, and IRF9), or the activation of NF-κB,

Antimicrobial and antiviral activity of NOS2

The antimicrobial and antiviral activity of NOS2 has been mostly studied with macrophages 14, 15, 19, 151, 152, but other myeloid (e.g., dendritic cells, neutrophils, and eosinophils) as well as non-myeloid cells (e.g., hepatocytes) can also exert NOS2-dependent effector functions as shown by in vitro killing assays, in vivo expression analyses, application of NOS2 inhibitors, the use of NOS2-deficient mice, or cell transfer studies 14, 25, 153, 154, 155, 156, 157. It is important to emphasize

NO and microbial escape of host defenses

Microorganisms have developed various constitutive or inducible mechanisms to resist oxidative and nitrosative stress, and also to evade killing by activated phagocytes. Classically, these include (i) the production of scavenger molecules (e.g., thiols), (ii) detoxifying enzymes (e.g., mycobacterial peroxiredoxins; truncated hemoglobin HbN of M. tuberculosis, which converts host-derived NO into nitrite; flavohemoglobin Hmp of e.g., Salmonella or Escherichia coli, which oxidizes –

NOS and myeloid cells

The expression of NOS2 by myeloid cells is associated with two major functional consequences: the acquisition and/or alteration of cell-intrinsic capabilities and phenotypes, and regulatory effects on neighboring immune cells. The first category is reflected not only by the NOS2-mediated antimicrobial activity of macrophages and other myeloid cells (as discussed above), but also by their cell-autonomous modulation of phagocytosis, expression of MHC class II and costimulatory molecules, antigen

NOS-mediated induction versus resolution of inflammation

Owing to its diverse sources, complex regulation, and multiple cellular and molecular targets and interaction partners, it is not surprising that NO has both stimulatory and suppressive properties in the immune system (see above and 15, 17). Which of these two categories will dominate the outcome of an immune response in a given in vivo situation, is hard to predict and difficult to analyze, especially because transgenic mice for cell type-specific and inducible NOS2 or NOS3 deletion are still

NO in disease and treatment

The striking antimicrobial and immunoregulatory effects of NO in vitro, and the expression of NOS2 and other NOS isoforms during infectious, autoimmune, chronic inflammatory, malignant, and degenerative diseases in humans and in animal models 14, 15, 42, 152, 228, 229, have stimulated immunologists and clinicians to investigate the functional role of NOS2 in vivo (e.g., by using transgenic mouse models) and to test the therapeutic application of NOS inhibitors or NO donors [230]. Because

Concluding remarks

In recent years our understanding of the role of NO in immunity has significantly changed. Originally conceived as a key effector mechanism of myeloid cells and the innate immune response, NOS2 must now also be considered as an integral component of the development, differentiation, and function of B and T lymphocytes, and also of non-hematopoietic cells. In addition to NOS2, NOS1 and NOS3 have to be taken into account as sources of immunomodulatory NO. Whereas in the past NO was selectively

Acknowledgements

The preparation of this manuscript and some of the work reviewed was supported by the Deutsche Forschungsgemeinschaft (SFB 643, project grant A6; GRK 1660), the Interdisciplinary Center for Clinical Research (IZKF) of the Universitätsklinikum Erlangen (project grants A49 and A61), the Emerging Field Initiative of FAU Erlangen-Nürnberg (project grant within the ‘Metal Redox Inorganic Chemistry’ consortium) and by the Dr Robert Pfleger Stiftung. I apologize to all authors, whose work could only

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Trends in Immunology

Feature ReviewNitric oxide synthase in innate and adaptive immunity: an update

Highlights

Section snippets

NO and the immune system: no end (yet) to new paradigms

Mammalian NO synthases

NO targets and signaling

Cytokines and microbial products

Antimicrobial and antiviral activity of NOS2

NO and microbial escape of host defenses

NOS and myeloid cells

NOS-mediated induction versus resolution of inflammation

NO in disease and treatment

Concluding remarks

Acknowledgements

Mammalian nitrite biosynthesis: mouse macrophages produce nitrite and nitrate in response to Escherichia coli lipopolysaccharide

Proc. Natl. Acad. Sci. U.S.A.

Induction of nitrite/nitrate synthesis in murine macrophages by BCG infection, lymphokines or interferon-γ

J. Immunol.

L-arginine is required for expression of the activated macrophage effector mechanism causing selective metabolic inhibition in target cells

J. Immunol.

Macrophage cytotoxicity: role of L-arginine deiminase and imino nitrogen oxidation to nitrite

Science

Cloning and characterization of inducible nitric oxide synthase from mouse macrophages

Science

Cloned and expressed macrophage nitric oxide synthase contrasts with the brain synthase

Proc. Natl. Acad. Sci. U.S.A.

Suppression of adjuvant-induced arthritis by selective inhibition of inducible nitric oxide synthase

Eur. J. Pharmacol.

L-N6-(1-iminoethyl)lysine potently inhibits inducible nitric oxide synthase and is superior to NG-monomethyl-arginine in vitro and in vivo

Eur. J. Pharmacol.

Altered responses to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase

Cell

Mice lacking inducible nitric oxide synthase are not resistant to lipopolysaccharide-induced death

Proc. Natl. Acad. Sci. U.S.A.

Altered immune responses in mice lacking inducible nitric oxide synthase

Nature

Effects of nitric oxide on the induction and differentiation of Th1 cells

Eur. J. Immunol.

Nitric oxide as a secretory product of mammalian cells

FASEB J.

The function of nitric oxide in the immune system

Nitric oxide and the immune response

Nat. Immunol.

Specificity of a third kind: reactive oxygen and nitrogen intermediates in cell signaling

J. Clin. Invest.

Regulation of lymphocytes by nitric oxide

Methods Mol. Biol.

Nitric oxide and redox mechanisms in the immune response

J. Leukoc. Biol.

Reactive oxygen and reactive nitrogen intermediates in the immune system

Vesicle membrane association of nitric oxide synthase in primary mouuse macrophages

J. Immunol.

Macrophage nitric oxide synthase associates with cortical actin but is not recruited to phagosomes

Infect. Immun.

Molecular mechanisms regulating macrophage response to hypoxia

Front. Immunol.

Nitric-oxide synthase-2 linkage to focal adhesion kinase in neutrophils influences enzyme activity and beta2 integrin function

J. Biol. Chem.

Epithelial inducible nitric-oxide synthase is an apical EBP50-binding protein that directs vectorial nitric oxide output

J. Biol. Chem.

Interaction of inducible nitric oxide synthase with rac2 regulates reactive oxygen and nitrogen species generation in the human neutrophil phagosomes: implication in microbial killing

Antioxid. Redox Signal.

Kinase suppressor of Ras-1 protects against pulmonary Pseudomonas aeruginosa infections

Nat. Med.

The physiologic aggresome mediates cellular inactivation of iNOS

Proc. Natl. Acad. Sci. U.S.A.

Nitric oxide synthase localization in the rat neutrophils: immunocytochemical, molecular, and biochemical studies

J. Leukoc. Biol.

Neuronal nitric oxide synthase regulates endothelial inflammation

J. Leukoc. Biol.

Expressional control of the ‘constitutive’ isoforms of nitric oxide synthase (NOSI and NOSIII)

FASEB J.

Induction of endothelial nitric oxide synthase in rat brain astrocytes by systemic lipopolysaccharide treatment

J. Biol. Chem.

The neuronal nitric oxide synthase is upregulated in mouse skin repair and in response to epidermal growth factor in human HaCaT keratinocytes

J. Invest. Dermatol.

The regulation and pharmacology of endothelial nitric oxide synthase

Annu. Rev. Pharmacol. Toxicol.

Nitric oxide in experimental joint inflammation. Benefit or detriment?

Feature Review
Nitric oxide synthase in innate and adaptive immunity: an update

Generation of HNO and HSNO from nitrite by heme–iron-catalyzed metabolism with H₂S