The biology of reactive intermediates in systemic lupus erythematosus

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune syndrome marked by autoantibody production. Innate immunity is essential to transform humoral autoimmunity into the clinical lupus phenotype. Nitric oxide (NO) is a membrane- permeable signaling molecule involved in a broad array of biologic processes through its ability to modify proteins, lipids, and DNA and alter their function and immunogenicity. The literature regarding mechanisms through which NO regulates inflammation and cell survival is filled with contradictory findings. However, the effects of NO on cellular processes depend on its concentration and its interaction with reactive oxygen. Understanding this interaction will be essential to determine mechanisms through which reactive intermediates induce cellular autoimmunity and contribute to a sustained innate immune response and organ damage in SLE.

Figure 1

The fate of NO and SO is dependent on the production of other RI and detoxifying pathways. NO is produced by NOS, which also produces SO when arginine is in short supply or if NOS is uncoupled. SO is also produced by inflammatory cells or cells under stress. NO reacts rapidly and preferentially with SO to form ONOO⁻. SO can be catalyzed to hydrogen peroxide (H₂O₂) by SO dismutase (SOD). H₂O₂ can undergo the Fenton reaction with Fe(II) to form OH which is converted into water by catalase. Myeloperoxidase found in neutrophils and other cells converts H₂O₂ to HOCl.

Figure 2

The actions of NO on biologically relevant molecules. NO can nitrosylate thiol amino acids in proteins or peptides to form nitrosothiols. It can nitrosylate iron in p450 enzymes and guanylate cyclase to alter enzyme activity. NO also acts as a radical scavenger of SO (SO or O₂−). When this latter reaction occurs, oxidative stress occurs through the action of ONOO⁻, which itself can nitrate protein tyrosines and DNA, a process that can alter enzyme function and increase immunogenicity of DNA and proteins/peptides. ONOO⁻ and NO₂ can oxidize lipids to form mediators of inflammation. Finally, ONOO⁻ can as act as a peroxide substrate to increase the activity of enzymes such as COX.