Adipokines: role in local and systemic inflammation of rheumatic diseases

KEYWORDS:

• Adipokines
• Rheumatic diseases
• inflammation
• disease activity
• treatment target

1. Introduction

Adipokines are cytokine-like molecules that were primarily thought to be produced by adipocytes. However, under pathological conditions, predominantly, immune cells secrete and largely contribute to increased local and sometimes also systemic levels of adipokines. In the past decade, the role of adipokines has been extensively studied in chronic inflammation, cancer, and other various conditions, including systemic rheumatic diseases. Adipokines modulate function of different tissues and cells, and in addition to energy homeostasis and metabolism, amplify inflammation, immune response, and tissue damage. In general, adipokines are elevated in systemic rheumatic diseases compared with control subject and associate with inflammatory status. Several adipokines are involved in the pathogenesis of rheumatic diseases and are also studied as surrogate biomarkers. In this editorial, the role of adipokines as biomarkers of disease activity, further prognosis and treatment outcome or their potential implication as therapeutic targets in systemic rheumatic diseases will be discussed.

Adipokines represent a large group of heterogeneous peptides with multiple functions that are primarily produced by adipocytes [1]. However, under pathological conditions, resident tissue cells and predominantly immune cells can contribute to local as well as systemic upregulation of adipokines [2]. Initially, adipokines were thought to be involved in energy homeostasis and metabolism, however, for well over a decade, adipokines have been shown to be implicated in chronic inflammation, cancer, and other various conditions [2]. Several adipokines have been demonstrated to modulate immune response and extracellular matrix damage. In this context, the role of several adipokines, including leptin, adiponectin, resistin, visfatin, chemerin, vaspin, omentin, and others, have been studied, particularly in connection with rheumatic diseases [3]. Adipokines can be secreted into the blood circulation and some may serve as biomarkers of disease activity, disease outcome, and treatment response, or may even become potential therapeutic target(s) [4,5].

2. Adipokines as biomarkers linking obesity and rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune disease associated with persistent synovial and systemic inflammation leading to joint damage, disability, and increased cardiovascular burden. Although the pathogenesis of RA remains incompletely understood, the growing evidence suggests that underlying pathology starts outside the joints.

Obesity is associated with low-grade inflammation and represents a risk factor for the development of several well-known diseases, including cardiovascular diseases, metabolic syndrome-related disorders, and various cancers, but also some rheumatic diseases [6]. Some studies showed association between preceding obesity in autoantibody positive individuals, including increased birth weight, and the onset of RA in the future [7,8]. On the other side, there is some evidence that obese patients with early RA develop less joint erosions and have slower structural progression over time [9].

Overweight cannot completely explain development or progression of RA suggesting that altered production of adipose tissue-derived inflammatory molecules may directly contribute to activation of immune system and retardation of joint damage. Recent findings suggest that adipokines, either released from adipose tissue or joint compartment, may be active players involved in these processes [3]. For instance, development of clinically manifest arthritis in autoantibody-positive individuals at risk of developing RA was associated with baseline serum vaspin levels [10]. Further, adiponectin levels, which are lower in obese subjects, were characterized as a potential link between high adiposity and decreased joint damage in RA [11].

In general, serum levels of adipokines are higher in RA patients compared to control (non-RA) subjects and are associated with inflammatory state of the disease [2–4]. There is evidence that adiponectin (in contrast to metabolic disorders) and some other adipokines, particularly visfatin and resistin, have a proinflammatory and joint-destructive role in RA by inducing proinflammatory cytokines, chemokines, and matrix degrading enzymes in synovial fibroblasts, lymphocytes, chondrocytes, and endothelial cells [12]. However, in some cases, the systemic effect of some adipokines may be different from that found in the joint. In this regard, in RA patients with severe disease despite using anti-TNF therapy, an independent negative correlation of high-grade inflammation with plasma adiponectin concentrations was found [13]. Low adiponectin concentrations further correlated independently with atherogenic dyslipidemia and high plasma glucose. These findings are similar to those previously reported in non-RA subjects and raise the possibility that low circulating adiponectin concentrations may be involved in cardiovascular disease in RA [13].

It may be suggested that local upregulation of adipokines by activated immune as well as resident tissue cells within the adipose tissue and/or synovial joints can contribute to increased systemic levels of some adipokines that may either precede RA development or may be associated with disease activity and further structural progression of RA.

3. The role of adipokines in other systemic rheumatic diseases

Apart from the involvement in RA, adipokines may also play a role in other systemic rheumatic diseases. For instance, while elevated serum resistin levels were associated with markers of inflammation, visfatin levels independently predicted subsequent progression of radiographic structural damage of the spine (syndesmophyte formation) in patients with ankylosing spondylitis [14]. Although visfatin levels were not associated with disease activity and functional impairment, the authors speculated that visfatin can directly affect osteoblasts to stimulate bone remodeling in ankylosing spondylitis. In addition, adiponectin levels and metabolic syndrome correlated with an increased burden of skin and joint inflammation in patients with psoriatic arthritis [15]. Adipokines are also implicated in the pathogenesis of nonrheumatic inflammatory diseases. With respect to this, a correlation between serum leptin levels, metabolic syndrome features, and inflammation was found in patients with moderate-to-severe psoriasis [16]. On the other hand, in these patients, resistin correlated with inflammation and disease severity [16].

We have recently found increased local expression of visfatin in myositic muscle tissue and an association between increased serum visfatin levels and muscle disease activity in patients with idiopathic inflammatory myopathies [17]. While visfatin levels did not correlate with muscle enzymes, but rather with inflammatory markers in myositis patients, it may speculated that visfatin is more likely associated with inflammatory response rather than with direct muscle damage. Furthermore, adiponectin serum levels were inversely associated with skin fibrosis and it was characterized to have a protective role in skin- and atherosclerosis-related changes during systemic sclerosis [18]. Some adipokines, namely leptin, were also demonstrated to play a role in systemic lupus erythematosus-related cardiovascular diseases [19].

Taken together, adipokines are considered as biomarkers regulating inflammation and immune response that may underlie their association with systemic rheumatic diseases. However, further studies are needed to elucidate whether adipokines are involved in the pathology of systemic rheumatic diseases or whether they only reflect altered immune response without specific role.

4. Adipokines as treatment targets in systemic rheumatic diseases

In general, some of these adipokines have proinflammatory and pro-destructive effects [3], and since they can modulate function of several effector cells, it can be speculated that targeted therapies against adipokines should become future treatment option for some disorders, including rheumatic diseases. Resistin is significantly upregulated particularly at sites of local inflammation, can modulate several molecular pathways involved in metabolic, inflammatory, and autoimmune diseases [2]. Although not yet demonstrated, one would expect that resistin might be a suitable target for treatment of inflammatory rheumatic diseases. With respect to effective treatment in an experimental model of arthritis, data are available for visfatin [5]. Reduced arthritis severity, comparable to tumor necrosis factor (TNF) blockade inhibitor (etanercept), and decreased proinflammatory cytokine secretion in affected joints, has been demonstrated for visfatin inhibitor [5]. Progranulin, a novel adipokine mediating insulin resistance and obesity, has been identified as an autocrine growth factor for cancer cells and fibroblasts. We have recently shown significant upregulation of progranulin in synovial tissue and synovial fluid as well as an association between circulating progranulin levels, disease activity, and functional impairment in patients with RA [20]. Previously, administration of progranulin prevented inflammation in several arthritis mouse models, probably via direct binding to TNF receptors [21]. In agreement with this finding, Abella et al. [22] recently demonstrated that progranulin counteracts IL-1 and TLR4-driven inflammatory response in human and murine chondrocytes, which may potentially have a therapeutic implication in osteoarthritis.

Further studies, however, are required to investigate, whether targeting these or other adipokines are of any potential therapeutic benefit. It needs to be stressed that adipokines play also a role in various human physiological functions and their modulation could thus be associated with deleterious side effects.

5. Conclusions

Taken together, adipokines belong to a large group of cytokine-like molecules that are produced not only by adipocytes, but largely by immune cells and resident tissue cells and can, in certain circumstances, amplify inflammation, immune response, and tissue damage. Some adipokines thus play a significant role in the pathogenesis of immune-mediated disorders like RA, spondyloarthritis, systemic lupus erythematosus, and probably other autoimmune rheumatic diseases as well as degenerative rheumatic disorders such as osteoarthritis [23]. With respect to the latter, it can be suggested that the association between obesity and osteoarthritis may well be triggered by adipokine dysregulation. Thereby, adipokines may become potential candidate molecules for the development of targeted therapies for immune-mediated diseases. In addition, some adipokines are associated with an increased inflammatory state and are suggested as biomarkers of disease activity, treatment response, and disease outcome. On the other side, as there are some partial findings [24], further studies are still required to elucidate the role of adipokines in rheumatic diseases.

Declaration of interest

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This work was supported by a project of the Ministry of Health of the Czech Republic (MHCR) for conceptual research development No. 023728.