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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Animals
  • Arthritis, Psoriatic / etiology*
  • Arthritis, Psoriatic / metabolism*
  • Arthritis, Psoriatic / pathology
  • Disease Models, Animal
  • Gene Expression
  • Humans
  • Immunity, Innate*
  • Interleukin-17 / metabolism*
  • Interleukin-1alpha / metabolism
  • Lipopolysaccharide Receptors / metabolism
  • Lymphocytes / immunology*
  • Lymphocytes / metabolism*
  • Macrophages / immunology*
  • Macrophages / metabolism*
  • Mannans / immunology*
  • Mice
  • Mice, Transgenic
  • Nitric Oxide / metabolism
  • Nitric Oxide Synthase Type II / genetics*
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism


  • Interleukin-17
  • Interleukin-1alpha
  • Lipopolysaccharide Receptors
  • Mannans
  • Nitric Oxide
  • Nitric Oxide Synthase Type II