期刊
SCIENCE ADVANCES
卷 4, 期 5, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.aas9864
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资金
- Knut and Alice Wallenberg Foundation [KAW 2015.0063]
- Swedish Association against Rheumatism [R-757331]
- Swedish Research Council [2015-02662]
- Swedish Foundation for Strategic Research [RB13-0156]
- European Union Innovative Medicine Initiative project BeTheCure [115142]
- German Federal Ministry of Education and Research ArthroMark [4, 01 EC 1009C]
- Federal State of Hesse (LOEWE-project, IME Fraunhofer Project Group TMP at Goethe University)
- Fonds de recherche du Quebec [27532]
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-gamma-stimulated monocyte subsets from patients with PsA compared to healthy controls. Nos2-dependent interleukin-1 alpha (IL-1 alpha) 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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