The Ncf1 mutation impairs superoxide anion production by the nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) complex ( 13, 14). The disease of MIP is more severe in mouse strains carrying a mutation in the neutrophil cytosol factor 1 ( Ncf1) gene ( 2). Recent clinical studies on blocking agents of various steps in the IL-17 pathway have demonstrated its crucial role in both Ps and PsA ( 5), but the triggering mechanisms and modifiers, as well as involvements of different T cell types, have not yet been clarified. Classical αβ T cells and various types of innate T cells may secrete IL-17 and be closely involved in the pathogenic IL-17 pathways. These data and more recent results from murine experimental models of Ps ( 7), as well as human studies demonstrating the presence of various types of innate T cells in psoriatic skin ( 8), suggest that these innate effectors play important roles in psoriatic plaque formation. However, conditional analysis of large case control data sets uncovered additional Ps risk alleles in loci encoding nonclassical MHC class I molecules ( 6). This traditional view of Ps is supported by the strong association with the HLA-C*0602 allele ( 6). Ps is a heterogeneous chronic disease driven by major histocompatibility complex (MHC)–restricted T cells operating through the IL-17/IL-22/IL-23 signaling pathway ( 5). Ps has been widely regarded as immune-mediated disease of the skin that is associated in approximately one-third of the patients with the development of PsA. We conclude that Nos2-derived NO by tissue macrophages promotes MIP, in contrast to the protective effect by ROS. Nos2-dependent interleukin-1α (IL-1α) release from skin macrophages was essential for arthritis development by promoting IL-17 production of innate lymphoid cells. NOS2 expression was also up-regulated in lipopolysaccharide- and interferon-γ–stimulated monocyte subsets from patients with PsA compared to healthy controls. MIP was suppressed by either deletion of Nos2 or inhibition of NO synthases with NG-nitro- l-arginine methyl ester, demonstrating that Nos2-derived NO is pathogenic. Using a mouse model of mannan-induced Ps and PsA (MIP), where macrophages play a regulatory role by releasing reactive oxygen species (ROS), we found that NO was detectable before disease onset in mice, independent of a functional nicotinamide adenine dinucleotide phosphate oxidase 2 complex. Previous identification of the inducible nitric oxide synthase (NOS2) gene as a risk allele for psoriasis (Ps) and psoriatic arthritis (PsA) suggests a possible pathogenic role of nitric oxide (NO).
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