Elsevier

Cytokine

Volume 49, Issue 1, January 2010, Pages 24-29
Cytokine

Expression of MDC/CCL22 and its receptor CCR4 in rheumatoid arthritis, psoriatic arthritis and osteoarthritis

https://doi.org/10.1016/j.cyto.2009.10.005Get rights and content

Abstract

The pathogenesis of rheumatoid arthritis (RA) and psoriatic arthritis (PsA) involves an abnormal chemokine regulation. The chemokine receptor CCR4 is necessary for T cell migration to the skin. We, therefore, studied if CCR4 and its ligand macrophage-derived chemokine (MDC/CCL22) could participate in spreading the disease between skin and joints by examining RA, PsA and osteoarthritis (OA) patients. In synovial fluid from RA and PsA patients we observed a significantly higher MDC/CCL22 level compared to OA patients. Additionally, the MDC/CCL22 protein was found to be elevated in RA and PsA plasma compared to OA and healthy volunteers. Flow cytometry revealed that most CD4+CCR4+ lymphocytes also co-expressed CD45RO. Neither the MDC/CCL22 level nor the expression of CCR4 correlated to CRP. Immunohistochemistry of the RA and OA synovial membrane demonstrated CCR4 to be expressed by mononuclear cells and endothelial cells. Our results show that MDC/CCL22 is present within the synovial membrane of RA and OA patients and in high amount in the synovial fluid of patients with RA and PsA. This will enable migration of CCR4 expressing memory cells supporting that MDC/CCR4 could play a role in attracting skin specific memory T cells to the joints.

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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