Spontaneous and aging-dependent development of arthritis in NADPH oxidase 2 deficiency through altered differentiation of CD11b+ and Th/Treg cells

Abstract

Emerging evidence indicates that NADPH oxidase (NOX) and its reactive oxygen species (ROS) products modulate a variety of cellular events, including proliferation, differentiation, and apoptosis. In this study, we investigated the functions of NOX2 and ROS in immune modulation using NOX2 knockout (KO) mice. Interestingly, NOX2 KO mice spontaneously developed arthritis with onset at 6-7 wk of age and high incidence (60%) at 15-18 wk of age. Arthritis severity in NOX2 KO mice was proportionally increased with age and higher in females than in males. Bone destruction was confirmed by microcomputed tomography scanning and histological analyses of joints. Inflammatory factors, including TNF-α, IL-1β, and RANKL, and serum level of anti-type II collagen IgG were significantly increased in NOX2 KO mice. In addition, NOX2 deficiency perturbed the immune system upon aging. NOX2 KO mice demonstrated preferred development of CD11b+Gr-1+ myeloid cells with profound production of proinflammatory cytokines and augmented expression of IL-17 through the activation of STAT3 and RORγt in vivo. NOX2 deficiency increased differentiation of effector Th cells in vitro and decreased CD25+FoxP3+ Treg cells both in vitro and in vivo. Furthermore, adoptive transfer of NOX2-deficient CD4 + T cells into RAG KO mice increased arthritic inflammation compared with WT cells. These results demonstrated that NOX2 deficiency affected the development of CD11b+ myeloid cells and Th17/Treg cells, and thus promoted inflammatory cytokine production and inflammatory arthritis development, strongly supporting a crucial role for ROS generation in the modulation of Th17/Treg cell development and its related inflammatory immune response upon aging.rheumatoid arthritis | myeloid-derived suppressor cell

p47 -Nox2-dependent ROS Signaling Inhibits Early Bone Development in Mice but Protects against Skeletal Aging

“…However, literature reports suggest that a reduction in ROS levels and signaling may also be detrimental (5,6). For example, in the musculoskeletal system, decreased ROS concentrations have been shown to promote inflammation (6).…”

Hyperbaric Oxygen Therapy (HBOT) as a Therapeutic Option for Patients with Atopic Dermatitis (AD) – Own Experiences and Literature Review

“…These cells -depending on current ROS tissue status and expression of one of the regulatory moleculesmay differentiate in two directions: FoxP3 + Tregs (in the case of IDO expression) or TH17 (in the case of HIF-1α expression), where an advantage of differentiation in one direction results in the simultaneous inhibition of differentiation in the opposite direction [14,54,55,58,59]. These are important observations, considering the studies conducted by Faleo et al, who found that FoxP3 + Tregs may be involved in the mechanism of preventive effect of HBOT in an animal model (NOD mice) of autoimmune diabetes [21].…”

Roles of Reactive Oxygen Species in Rheumatoid Arthritis Pathogenesis

“…ROS have been shown to regulate autoimmune responses. Impairment of Nox2-dependent ROS generation in neutrophil cytosolic factor 1 (Ncf1)-mutated mice results in enhanced disease severity in several different animal models of arthritis [11,18,19]. Macrophage-restricted expression of functional Ncf1 restored arthritis resistance in a CIA model but not in a T cell-independent anti-collagen antibody-induced arthritis model.…”

“…In addition, activation of naïve T cells from Nox2-deficient mice exhibited a skewed Th17 phenotype [19]. The immediate-early response gene X-1 (IEX-1, also known as IER3) is involved in preventing the production of ROS in mitochondria.…”

“…Oxidative stress has already been shown to be involved in autoimmune responses. Surprisingly the p47phox subunit of Nox2 was first discovered as a protective factor in arthritis models, which suggested that Nox2-originated oxidative bursts suppressed autoimmune T cells [11,18,19]. ROS generation was proposed to regulate the expression of inflammatory cytokines and chemokines and to affect tissue damage in RA [20].…”