Adiponectin Enhances Th17 Actions – Arthritis
A study published in the online Scientific Reports journal reveals a new maladaptive and pro-inflammatory effect of adiponectin – its ability to increase T helper (Th)17 immune responses and the expression of receptor activator of nuclear factor-κB ligand (RANKL) in an animal model of arthritis.
Although the precise etiology of rheumatoid arthritis (RA) still remains elusive, substantial evidence has suggested that T cells, B cells and the complex interaction of multiple pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-1 and IL-17, play a critical role in the pathophysiology of RA.
Adipose tissue or the adipocytes in joints have long been considered as none-bioactive cells and only devoted to energy storage. During recent years, there is growing evidence that adipokines produced by white adipose tissue including adiponectin (AD), leptin, visfatin and resistin play an important role in regulating immune and inflammatory processes.
Adiponectin is the most abundant adipokine, being present at concentrations of 5–30 μg/ml in circulation. It is produced prevalently by adipose tissues, but is also secreted by skeletal muscles, cardiacmyocytes, and endothelial cells.
Adiponectin, a protein secreted mostly by adipocytes (fat cells), is a hormone involved in regulation of lipids and glucose metabolism. It is very abundant in plasma and is expressed at high levels by lean, healthy individuals, and in the bloodstream it accounts for approximately 0.01% of all plasma protein.
Both pro-and anti- inflammatory effects of adiponectin have been described. Interestingly, low levels of adiponectin in obesity, type II diabetes, and metabolic disorders, but high levels of adiponectin are reported in heart failure, hypertension, and chronic inflammatory and autoimmune diseases such as systemic lupus erythematosus, type I diabetes and rheumatoid arthritis (RA).
Previous research indicates the involvement of adiponectin in RA, including it’s high expression in the inflamed synovial joints, and a correlation with progressive bone erosion and severity of RA. Moreover, serum adiponectin level appears to be a surrogate biomarker of initial radiographic disease progression in patients with early rheumatoid arthritis.
Previous research also indicates that adiponectin activates dendritic cells, leading to Th1 and Th17 phenotypes and polarization. The Th17 cells-related cytokine IL-17, is a key player in inflammation and autoimmunity, while RANKL is critically involved in bone erosion.
In the Scientific Reports study, Xiaoxuan Sun and colleagues from the Department of Rheumatology and Immunology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu, China, studied the role of adiponectin, the link between RANKL, IL-17 and bone erosion in mice with collagen-induced arthritis (CIA).
The authors report that local AD, IL-17 and RANKL levels are increased during CIA development. Furthermore, the intra-articular injection of AD into the knee joint of CIA animals aggravates arthritic progression and bone erosion, accompanied by an increased number of Th17 cells and a high expression of RANKL in joint tissues.
Importantly, the researchers provide evidence that adiponectin most likely is able to promote the Th17 cell differentiation through up-regulation of ROR-γt, IL-22 and IL-23 expression.
It appears that this study identifies a novel maladaptive role of AD, namely, the promotion of local and highly pathogenic Th17 cell immune responses in experimental arthritis.
The authors conclude that their study suggests that in arthritis, the locally increased AD levels may contribute to inflammation and bone erosion by enhancing Th17 responses and RANKL expression.
In summary, this study has demonstrated that AD can promote the differentiation of naïve T cell to Th17 cell and upregulate RANKL/OPG ratio, resulting in an enhanced synovitis and bone erosion in CIA models. These findings reveal a novel role of AD in mediating the development of autoimmune arthritis in mice.
Source: Sci Rep, 2015 Jun 11;5:11296. doi: 10.1038/srep11296.
Read More: Scientific Reports
