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

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.

Figure 1

NO synthesis from arginine by iNOS and cofactors. Electrons (e–) are donated by NADPH to FAD and FMN in the reductase domain. This step requires Ca²⁺ (much higher levels for eNOS and nNOS than for iNOS) and calmodulin. Two cycles of electrons are then transferred by these carriers to heme iron in the oxygenase domain of the adjacent dimer. This reaction is similar to that in P450 enzymes. The role of tetrahydrobiopterin (BH₄) in this process is unclear, but it may assist in the coupling of NADPH oxidation and NO formation, thus preventing SO formation. With arginine and O₂ as substrates, donated electrons then catalyze two reaction steps, the formation of N^ω-hydroxy-l-arginine (NHA) followed by conversion of NHA to NO and citrulline. SO is formed when l-arginine substrate is limited, and electrons from the reductase domain react directly with oxygen [3]. This figure is reprinted from [77].

Figure 2

Cellular microenvironment changes the fate of NO. After synthesis by iNOS, eNOS, or nNOS, NO freely diffuses across membranes, forming a concentration gradient. Within this microenvironment also exists a redox gradient (represented by the black rectangle) formed by the presence of oxidant/reductant-coupled species. The redox state thus determines whether NO ultimately forms what are usually benign vs. pathogenic RNI. As an example, when formed in the presence of O₂, NO can oxidize to NO₂ and NO₃. Whereas when formed in the presence of superoxide (SO or O₂^•−), NO oxidizes to form peroxynitrite (ONOO⁻) [12]. This figure is reprinted from [77].