Elsevier

Clinical Immunology

Volume 121, Issue 3, December 2006, Pages 243-250
Clinical Immunology

Short Analytical Review
The biology of nitric oxide and other reactive intermediates in systemic lupus erythematosus

https://doi.org/10.1016/j.clim.2006.06.001Get rights and content

Abstract

Formation of reactive nitrogen and oxygen intermediates (RNI and ROI) is an essential part of the innate immune response. Markers of systemic RNI production are increased in the setting of systemic lupus erythematosus (SLE) activity. Several lines of evidence suggest mechanisms through which the activity of inducible nitric oxide synthase (iNOS) is pathogenic in SLE, including the ability of peroxynitrite (ONOO, a product of iNOS activity) to modify proteins, lipids, and DNA. These modifications can alter enzyme activity and may increase the immunogenicity of self antigens, leading to a break in immune tolerance. In humans, observational data suggest that overexpression of iNOS and increased production of ONOO lead to glomerular and vascular pathology. Therapies designed to target iNOS activity or scavenge ROI and RNI are in development and may provide the means to reduce the pathogenic consequences of ROI and RNI in SLE.

Introduction

Systemic lupus erythematosus (SLE) is a classic autoimmune disease defined by the formation of immune complexes with autoantigens. However, the innate immune system plays an integral role in propagating inflammatory responses initiated by this acquired immune response. An important part of that innate immune response is the production of reactive nitrogen and oxygen intermediates (RNI and ROI). One of the most widely studied RNI, nitric oxide (NO), is overproduced in the setting of lupus activity. Its pathogenic potential in lupus or any other disease lies largely in the extent of its production and the proximity of its synthesis to ROI such as superoxide (SO). NO and SO react to form peroxynitrite (ONOO), a much more reactive and potentially pathogenic molecule. There is convincing evidence in murine lupus nephritis that inducible nitric oxide synthase (iNOS) activity increases with the progression of disease and leads to glomerular, joint, and dermal pathology. In addition, ONOO-mediated modifications of proteins and DNA may increase the immunogenicity of these self antigens, leading to a break in immune tolerance. Redox-sensitive signaling pathways can be activated by the production of ROI/RNI, leading to further transcription of inflammatory mediators. In humans, there are observational data suggesting that overexpression of iNOS and increased production of ONOO lead to glomerular and vascular pathology. Therapies designed to target iNOS activity or scavenge ROI/RNI have not been tested in humans in part due to concerns over the specificity of many available compounds for their targets. However, several new compounds are in development that offer promise for human trials.

Section snippets

Biology of reactive nitrogen intermediates (RNI)

Free radicals are highly reactive molecules with unpaired electrons. They represent an important arm of host defense against a variety of pathogens [1]. Not only are reactive oxygen and nitrogen intermediates (RONI) directly toxic to invading pathogens, they activate redox-sensitive signaling pathways such as nuclear factor-kappa B (NF-κB) and activator protein-1 (AP-1) that in turn regulate the transcription of proinflammatory proteins such as cytokines [2]. In systemic lupus erythematosus

Observational studies

While iNOS activity can suppress parasitemia or tumor growth, its overexpression in the setting of lupus disease activity appears to lead to organ damage and an altered immune response. Several studies involving murine models of lupus support this hypothesis. Both MRL/MpJ-Faslpr/J (MRL/lpr) and (New Zealand Black×New Zealand White)F1 (NZB/W) mice develop spontaneous proliferative lupus nephritis. MRL/lpr mice developed increasing levels of urine NO metabolites (nitrate + nitrite or NOX) in

Manipulation of iNOS in murine lupus

Several studies utilizing competitive inhibitors of iNOS suggest that iNOS activity is pathogenic in murine lupus. Inhibiting iNOS activity in MRL/lpr mice before disease onset with the nonspecific arginine analog l-NG-monomethyl-l-arginine (l-NMMA) reduced 3NTyr formation in the kidney, partially restored renal catalase activity, and inhibited cellular proliferation and necrosis within the glomerulus [16], [17], [22]. This effect occurred in the absence of a change in immunoglobulin or

Potential mechanisms for pathogenicity of RNI suggested by studies in murine models of lupus

The mechanisms through which iNOS activity may be pathogenic in SLE has been studied in animal models and in vitro (Table 1). As mentioned above, ONOO, a byproduct of iNOS activity, can nitrate protein amino acids and change the catalytic activity of enzymes. One such enzyme, catalase, serves to protect host tissues from free radical attack [17]. In vascular tissue, prostacyclin synthase [29] and eNOS [30] are inactivated by ONOO, leading to vasoconstriction. These observations suggest that

Observational studies

While there is compelling evidence for aberrant reactive nitrogen production in the pathogenesis of murine lupus nephritis, the lack of appropriately selective iNOS inhibitors for human use limits human studies to observation. Increased expression of the iNOS enzyme has been reported in multiple tissues among SLE subjects. Several laboratories have described increased expression in the glomeruli of subjects with proliferative lupus nephritis [38], [39], [40]. In one study, glomerular iNOS

Translation of current knowledge into human therapies

Expression of iNOS is an important arm of the innate immune response when it occurs in the setting of infectious stimuli. In the setting of lupus, its expression occurs outside of this context with additional expression in non-immune cells such as endothelial cells and keratinocytes [42]. It is generally accepted that ONOO is one of the more pathogenic and abundant of the RNI derived from iNOS activity. Both eNOS and nNOS-derived NO can combine with SO produced in close proximity to produce

Conclusion

Production of NO from constitutive NOS signals for vasodilation and neurotransmission under physiologic circumstances. Increased expression of iNOS in response to infection or malignancy is an important arm of the innate immune response. In such circumstances, ONOO is often produced. However, increased expression of iNOS in response to inflammatory stimuli present in SLE may lead to increased tissue damage, altered enzyme activity, and increased expression of neoepitopes in self antigens.

References (78)

  • A. Furusu et al.

    Expression of endothelial and inducible nitric oxide synthase in human glomerulonephritis

    Kidney Int.

    (1998)
  • A. Kuhn et al.

    Aberrant timing in epidermal expression of inducible nitric oxide synthase after UV irradiation in cutaneous lupus erythematosus

    J. Invest. Dermatol.

    (1998)
  • M.R. Hobbs et al.

    A new NOS2 promoter polymorphism associated with increased nitric oxide production and protection from severe malaria in Tanzanian and Kenyan children

    Lancet

    (2002)
  • W. Xu et al.

    Survey of the allelic frequency of a NOS2A promoter microsatellite in human populations: assessment of the NOS2A gene and predisposition to infectious disease

    Nitric Oxide

    (2000)
  • B. Coles et al.

    Nitrolinoleate inhibits platelet activation by attenuating calcium mobilization and inducing phosphorylation of vasodilator-stimulated phosphoprotein through elevation of cAMP

    J. Biol. Chem.

    (2002)
  • C. Delles et al.

    Assessment of endothelial function of the renal vasculature in human subjects

    Am. J. Hypertens

    (2002)
  • L. Kirchner et al.

    Impaired cognitive performance in neuronal nitric oxide synthase knockout mice is associated with hippocampal protein derangements

    Nitric Oxide

    (2004)
  • E. Blasko et al.

    Mechanistic studies with potent and selective inducible nitric-oxide synthase dimerization inhibitors

    J. Biol. Chem.

    (2002)
  • H.M. Tse et al.

    Mechanistic analysis of the immunomodulatory effects of a catalytic antioxidant on antigen-presenting cells: implication for their use in targeting oxidation–reduction reactions in innate immunity

    Free Radical Biol. Med.

    (2004)
  • H. Ohmori et al.

    Immunogenicity of an inflammation-associated product, tyrosine nitrated self-proteins

    Autoimmun. Rev.

    (2005)
  • S. Habib et al.

    Acquired antigenicity of DNA after modification with peroxynitrite

    Int. J. Biol. Macromol.

    (2005)
  • J.D. Morrow et al.

    The isoprostanes: unique bioactive products of lipid peroxidation

    Prog. Lipid Res.

    (1997)
  • G.J. Southan et al.

    Selective pharmacological inhibition of distinct nitric oxide synthase isoforms

    Biochem. Pharmacol.

    (1996)
  • T.C. Zahrt et al.

    Reactive nitrogen and oxygen intermediates and bacterial defenses: unusual adaptations in Mycobacterium tuberculosis

    Antioxid. Redox Signal.

    (2002)
  • I. Rahman et al.

    Current concepts of redox signaling in the lungs

    Antioxid. Redox Signal.

    (2006)
  • W.K. Alderton et al.

    Nitric oxide synthases: structure, function and inhibition

    Biochem. J.

    (2001)
  • E. Karpuzoglu, S.A. Ahmed, Estrogen regulation of nitric oxide and inducible nitric oxide synthase (iNOS) in immune...
  • J. Lincoln et al.

    Nitric Oxide in Health and Disease

    (1997)
  • Human Proteome Resource Program, NOS2A in normal tissues; [accessed May 19, 2006], Available from:...
  • Y. Xia et al.

    Superoxide and peroxynitrite generation from inducible nitric oxide synthase in macrophages

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

    (1997)
  • S.A. Gaertner et al.

    Glomerular oxidative and antioxidative systems in experimental mesangioproliferative glomerulonephritis

    J. Am. Soc. Nephrol.

    (2002)
  • C.S. Boyd et al.

    Nitric oxide and cell signaling pathways in mitochondrial-dependent apoptosis

    Biol. Chem.

    (2002)
  • V. Mollace et al.

    Modulation of prostaglandin biosynthesis by nitric oxide and nitric oxide donors

    Pharmacol. Rev.

    (2005)
  • J.B. Weinberg et al.

    The role of nitric oxide in the pathogenesis of spontaneous murine autoimmune disease: increased nitric oxide production and nitric oxide synthase expression in MRL-lpr/lpr mice, and reduction of spontaneous glomerulonephritis and arthritis by orally administered NG-monomethyl-l-arginine

    J. Exp. Med.

    (1994)
  • T. Keng et al.

    Peroxynitrite formation and decreased catalase activity in autoimmune MRL-lpr/lpr mice

    Mol. Med.

    (2000)
  • J. Delgado Alves et al.

    Antiphospholipid antibodies are associated with enhanced oxidative stress, decreased plasma nitric oxide and paraoxonase activity in an experimental mouse model

    Rheumatology (Oxford)

    (2005)
  • V. Bremer et al.

    Role of nitric oxide in rat nephrotoxic nephritis: comparison between inducible and constitutive nitric oxide synthase

    J. Am. Soc. Nephrol.

    (1997)
  • T. Ohse et al.

    Modulation of interferon-induced genes by lipoxin analogue in anti-glomerular basement membrane nephritis

    J. Am. Soc. Nephrol.

    (2004)
  • Y. Takeda et al.

    Chemical induction of HO-1 suppresses lupus nephritis by reducing local iNOS expression and synthesis of anti-dsDNA antibody

    Clin. Exp. Immunol.

    (2004)
  • Cited by (71)

    • Long-term exposure to traffic-related air pollution and systemic lupus erythematosus in Taiwan: A cohort study

      2019, Science of the Total Environment
      Citation Excerpt :

      From the animal study, exposure to traffic-related PM pollutant enhanced the expression of inducible nitric oxide synthase (iNOS) (Bai et al., 2011). The overexpressed activity of iNOS may lead to exacerbated tissue damage in SLE (Oates and Gilkeson, 2006). Getting clues from epidemiological studies that assessed the associations between air pollution and autoimmune rheumatic diseases.

    View all citing articles on Scopus
    View full text