Zhong, J.J.ZhongScholz, T.T.ScholzYau, A.C.Y.A.C.Y.YauGuerard, S.S.GuerardHüffmeier, U.U.HüffmeierBurkhardt, H.H.BurkhardtHolmdahl, R.R.Holmdahl2022-03-052022-03-052018https://publica.fraunhofer.de/handle/publica/25672810.1126/sciadv.aas9864Previous 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). 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. 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. NOS2 expression was also up-regulated in lipopolysaccharide- and interferon-g-stimulated monocyte subsets from patients with PsA compared to healthy controls. Nos2-dependent interleukin-1a (IL-1a) release from skin macrophages was essential for arthritis development by promoting IL-17 production of innate lymphoid cells. We conclude that Nos2-derived NO by tissue macrophages promotes MIP, in contrast to the protective effect by ROS.en540571572journal article