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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.

Author information

1
Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm 171 77, Sweden.
2
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.
3
Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen 910 54, Germany.
4
School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China.

Abstract

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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