Short Analytical ReviewThe biology of nitric oxide and other reactive intermediates in systemic lupus erythematosus
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.
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