Expression of MDC/CCL22 and its receptor CCR4 in rheumatoid arthritis, psoriatic arthritis and osteoarthritis
Introduction
Rheumatoid arthritis (RA) and psoriatic arthritis (PsA) are chronic, systemic, inflammatory diseases that affect multiple synovial joints. The inflamed synovial membrane is characterized by massive infiltration of lymphocytes and macrophages and increased vascularity resulting in destruction of cartilage and underlying bone structure with severe disability as a consequence. RA can affect a number of organs including the skin [1], [2]. Psoriasis primarily affects the skin, but gives rise to joint disease in 5–39% of the patients [3], [4], [5].
The recruitment of effector cells is an important step in the development of an inflammatory response and is orchestrated in part by chemokines. Chemokines are responsible for selective recruitment of cells expressing a specific receptor [6], [7].
The macrophage-derived chemokine (MDC)/CCL22 belongs to the CC family and is synthesized and secreted by macrophages, dendritic cells, osteoclasts, Burkitt’s lymphoma and EBV immortalized B cell lines [8], [9], [10]. It acts selectively on chronically activated lymphocytes by interacting with the CCR4 receptor, which also has Thymus and activation regulated chemokine (TARC)/CCL17 as its ligand [9], [11]. MDC/CCL22 and CCR4 have been shown to play a role in diseases in various organs including lungs and skin [12], [13], [14], [15]. Further, injection of MDC/CCL22 induces accumulation of CCR4 expressing T cells in vivo [6]. Traditionally, CCR4 has been described to be expressed preferentially on T cells belonging to the Th2 subpopulation [9], [11]. Recent studies have shown expression of CCR4 on Th17 cells as well as on regulatory T cells (Treg), making the understanding of this receptor even more complicated [16]. Expression of cutaneous lymphocyte antigen (CLA) has commonly been used to characterize skin-homing lymphocytes but not found to be increased in arthritis [17]. However, CCR4 expression has been found to be necessary for skin specific lymphocyte trafficking [18]. Furthermore, CCR4 is expressed by a subset of skin lymphocytes that are CLA negative [19]. These recent findings point to a much broader role of CCR4 and MDC/CCL22 in inflammation and not as a Th2 chemokine only.
We therefore wanted to further examine the expression of MDC/CCL22 and its receptor CCR4 in arthritis. We observed increased levels of MDC/CCL22 in the joints of RA and PsA patients, and located its receptor CCR4 on CD4+CD45RO+ memory T cells in the inflamed joints.
Section snippets
Collection of samples
Synovial membranes were obtained from patients with RA (n = 11) and OA (n = 7) at the time of joint replacement. The membranes were embedded in Tissue-Tek® OCT compound (Sakura, Torrance, CA, USA), snap frozen in liquid hexane, and stored at −80 °C until use. PsA synovial membranes were not included in this study as the joint destruction in PsA rarely lead to joint replacement. Punch biopsies from lesional psoriatic skin (n = 3) were obtained and treated as described above.
Synovial fluid and blood
Localization of MDC/CCL22 and CCR4 in synovial tissue
MDC/CCL22 and CCR4 are both strongly connected to skin inflammation. We confirmed that both MDC/CCL22 and CCR4 expressing cells are present in plaque psoriasis using immunohistochemistry (Fig. 1). We then progressed to examining synovial membranes from patients with RA and OA. MDC staining was evident in 10 of 11 RA patients and all OA patients (n = 7). In RA patients the MDC/CCL22 positive cells were scattered throughout the synovial tissue, localized to large, mononuclear cells and in OA
Discussion
In this study we examined the amount, localization and expression of MDC/CCL22 and its receptor CCR4 in RA, PsA and OA patients and controls. We are the first to report increased levels of MDC/CCL22 in the inflamed synovial fluid.
Spreading of disease, especially in the case of psoriasis, is still not fully elucidated. The skin involvement in psoriasis usually initiates in the second to third decade of life, whereas the joint symptoms often start 1–2 decades later, primarily in the knees and
Acknowledgments
We are grateful to Dr. Kouji Matsushima for providing the CCR4 antibody. This work was financially supported by “Danish Rheumatism Association” (Journal No. R49-A522-B55 and R25-A132-B55), “Danish Psoriasis Association”, “Danish Agency for Science, Technology and Innovation” (Journal No. 271-06-0792 and 271-06-0169), and the Danish Research school in In Vivo Pharmacology.
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2017, CytokineCitation Excerpt :CCL22 was also significantly increased in RA ECs compared to non-RA (p = 0.014). This relates to earlier work identifying CCL22 ‘scattered throughout’ RA synovium and CCR4, the CCL22 receptor, localised on ECs [23]. In the current study the increased presence of CCL22 in RA ECs indicates that it may have a role in the recruitment of inflammatory cells to the RA synovium such as monocytes and T lymphocytes.
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Shared first authorship.