A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä
Reactive Oxygen Species Regulate Both Priming and Established Arthritis, but with Different Mechanisms
Tekijät: Sareila Outi, Hagert Cecilia, Kelkka Tiina, Linja Marjo, Xu Bingze, Kihlberg Jan, Holmdahl Rikard
Kustantaja: Mary Ann Liebert, Inc. publishers
Julkaisuvuosi: 2017
Journal: Antioxidants and Redox Signaling
Lehden akronyymi: Antioxid Redox Signal
Vuosikerta: 27
Numero: 18
Aloitussivu: 1473
Lopetussivu: 1490
Sivujen määrä: 18
ISSN: 1523-0864
DOI: https://doi.org/10.1089/ars.2016.6981
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 ten days. Mice, in which Ncf1 had
been activated prior to immunization with type II collagen (CII),
developed only mild clinical symptoms of collagen-induced arthritis
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 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 humans and in 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 collagen-induced
arthritis, most likely via different mechanisms.
