Reactive Oxygen Species Regulate Both Priming and Established Arthritis, but with Different Mechanisms.

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Antioxid Redox Signal. 2017 Jun 1. doi: 10.1089/ars.2016.6981. [Epub ahead of print]

Reactive Oxygen Species Regulate Both Priming and Established Arthritis, but with Different Mechanisms.

O Sareila;C Hagert;T Kelkka;M Linja;B Xu;J Kihlberg;R Holmdahl

University of Turku, Turku, Finland. Informational and Structural Biology, Turku, Finland. Turku Doctoral Programme of Biomedical Sciences, Turku, Finland. Karolinska Institutet, Stockholm, Sweden. Uppsala University, Uppsala, Sweden.

Service type: Knock-in mice


Aims: Neutrophil cytosolic factor 1 (NCF1) is a key regulatory component of the phagocytic NOX2 complex, which produces reactive oxygen species (ROS). Polymorphism of the Ncf1 gene is associated with increased arthritis severity. In this study, we generated targeted Ncf1 knock-in mice with inducible Ncf1 expression and determined the critical time window during which the NOX2-derived ROS protect the mice from arthritis. Results: Targeted Ncf1 knock-in mice lacked NOX2-derived ROS, and in vivo allelic conversion of Ncf1 by the CreERT2 recombinase led to full protein expression and ROS production within 10 days. Mice in which Ncf1 had been activated before immunization with type II collagen (CII) developed only mild clinical symptoms of collagen-induced arthritis (CIA), whereas the ROS-deficient littermates had severe arthritis. The functional Ncf1 restricted the expansion of IL-17A-producing T cells specific for the immunodominant CII peptide. When the Ncf1 gene was activated after the priming phase, Ncf1-dependent protection from autoimmune arthritis was still observed, together with a reduced number of splenic monocytes but it was not associated with alterations in peptide-specific T cell response. The Ncf1-deficient mice expressed pronounced interferon signature, which could be normalized by conditional expression of Ncf1 and was also present in the Ncf1-mutated mouse during arthritis. Innovation and Conclusion: Ncf1 deficiency has been known to predispose to autoimmunity in both humans and rodents. Our in vivo results point to a regulatory role of NOX2-derived ROS not only during priming but also during the effector phase of CIA, most likely via different mechanisms. Antioxid. Redox Signal. 27, 1473-1490. Keywords: IFN-regulated gene expression; NADPH oxidase; Neutrophil cytosolic factor 1 (Ncf1); collagen-induced arthritis; interferon signature; reactive oxygen species (ROS).

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