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

Science Advances
Jianghong ZhongRikard Holmdahl

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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Citations

Dec 25, 2019·Antioxidants & Redox Signaling·Jianghong ZhongRikard Holmdahl
Feb 6, 2021·The Journal of Investigative Dermatology·Jianghong ZhongRikard Holmdahl
Jun 21, 2021·European Journal of Pharmacology·Yihong WanXingang Yao
Jul 15, 2021·Communications Biology·Jianghong ZhongRikard Holmdahl

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Methods Mentioned

BETA
PMA
flow cytometry
genotyping
Assay
biopsies
lavage

Software Mentioned

DIVA
FlowJo
MIP
Graph Prism
Macmini

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