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
Updates
2021
A 2021 study by Nan Che et al. reported that that adiponectin (AD) exacerbated collagen-induced arthritis (CIA) in mice by enhancing B cell proliferation and differentiation mediated by the PI3K/Akt1/STAT3 axis.
The investigators demonstrated that local intra-articular injection of AD promoted an earlier arthritic onset and exacerbated arthritis development in murine CIA. Importantly, they found an increased number of plasma cells in the joint tissue of CIA mice with intra-articular injection of AD.
Furthermore, the authors also found that AD promoted both proliferation and differentiation of B cells in cell culture. Mechanistically, AD induced the activation of PI3K/Akt1 and STAT3 and promoted the proliferation and differentiation of B cells. Thus, researchers discussed that their results revealed a previously unrecognized role of AD in enhancing B-cell response and driving autoimmune inflammation during CIA development.
Importantly the investigators speculated that local AD may stimulate B cell activation and differentiation into IgG-secreting plasma cells in the knee joint to produce anti-collagen antibodies. This, according to the authors, may represent a mechanism by which AD drives B-cell response in addition to its recognized function in promoting T-cell response, leading to aggravated arthritis progression during the pathogenesis of CIA.
2022
A 2022 study by Yani Wang et al. investigated the expression of adiponectin (AD) and AdipoR1 in synovial tissue of rheumatoid arthritis (RA) and osteoarthritis (OA) patients. Also, AdipoR1 was knocked down in human RASF cell line (MH7A) and CIA mice joints.
The investigators found that both the expression of AD and AdipoR1 were significantly higher in RA synovial tissue. Importantly, silencing AdipoR1 remarkably reduced lipopolysaccharides-induced proliferation and promoted the apoptosis of MH7A. Moreover, the researchers reported that the AdipoR1 knockdown inhibited the release of inflammatory factors in vitro.
In CIA mice, the authors found that local AdipoR1 inhibition effectively decreased joint inflammation and alleviated bone destruction via suppressing RANKL and RANKL/OPG ratio in vivo.
Thus, the investigators concluded that AdipoR1 signaling participated in the process of synovial inflammation and joint damage in CIA. Importantly, local AdipoR1 inhibition decreased joint inflammation and alleviated bone destruction in CIA. Thus, the authors speculated that local blockade of AdipoR1 might be a new target for the clinical treatment of RA.
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