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Sci Adv. 2018 May 16;4(5):eaas9864. doi: 10.1126/sciadv.aas9864. eCollection 2018 May.

Mannan-induced Nos2 in macrophages enhances IL-17-driven psoriatic arthritis by innate lymphocytes.

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Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm 171 77, Sweden.
Project Group Translational Medicine and Pharmacology, Fraunhofer Institute for Molecular Biology and Applied Ecology and Division of Rheumatology, University Hospital Frankfurt, Goethe University, Frankfurt am Main 605 90, Germany.
Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen 910 54, Germany.
School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China.


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). 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-γ-stimulated monocyte subsets from patients with PsA compared to healthy controls. Nos2-dependent interleukin-1α (IL-1α) 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.

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