ROS-dependent SOCS3 upregulation disrupts regulatory T cell stability during autoimmune disease development
Hiroki Satooka, Yuzuki Nakamura, Takako Hirata
Abstract
Autoimmune diseases including rheumatoid arthritis (RA) are often associated with high levels of reactive oxygen species (ROS); however, the ROS targets in autoimmunity are diverse and unclear. Using collagen-induced arthritis (CIA) mice as a model for RA, we report that antioxidants markedly suppress joint inflammation, antibody production, and effector T cell responses. We found that the frequency of CD4 + regulatory T cells (Tregs) was reduced in CIA mice, which was reversed by antioxidant treatment, and SOCS3, known to be associated with Treg instability, was upregulated in Tregs from both RA patients and CIA mice. Mechanistically, SOCS3 upregulation was induced by ROS-dependent PTEN oxidation and the resultant Akt/mTOR/STAT3 activation. We further showed that the source of ROS involved in this pathway is NADPH oxidase 2 (Nox2). Nox2 expression was upregulated in Tregs from CIA mice, and Nox2 transduction induced a decrease in Treg frequency that depended on SOCS3 upregulation. This study thus provides a mechanistic understanding of ROS-induced Treg instability and suggests that ROS-dependent disruption of Treg homeostasis underlies the development and progression of autoimmune diseases. • Antioxidants suppress T and B cell–dependent induction phase of a CIA model. • ROS decrease Treg frequency through SOCS3 upregulation in CIA mice. • ROS-mediated PTEN oxidation induces SOCS3 upregulation via Akt/STAT3 activation. • Nox2 upregulated in Tregs is the source of ROS.