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Upregulated expression of CCR3 in rheumatoid arthritis and CCR3-dependent activation of fibroblast-like synoviocytes

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Abstract

It is recognized that CC chemokine receptor 3 (CCR3) is associated with numerous inflammatory conditions and fibroblast-like synoviocyte (FLS) invasiveness correlates with articular damage in rheumatoid arthritis (RA). However, little is known of the expression and action of CCR3 on FLS in RA. In the present study, we investigated the expression of CCR3 on dispersed synovial tissue and peripheral blood cells in RA and influence of eotaxin-1 on FLS functions by using flow cytometry analysis, FLS challenge, and real-time PCR techniques. The results showed that approximately 7.0 % dispersed synovial cells are CCR3+ cells. Among those CCR3+ cells, 38.1, 23.8, and 20.6 % cells are CD90+CD14−CD3− (representing FLS), CD14+, and CD8+ cells, respectively, indicating that FLS is one of the major populations of CCR3+ cells in the synovial tissue of RA. In peripheral blood, CD14+ CCR3+ cells are elevated, but CD8+CCR3+ cells are reduced in RA. It was found that eotaxin-1 induced upregulated expression of CCR3 and matrix metalloproteinase (MMP)-9 messenger RNAs (mRNAs) in FLS. Since an antagonist of CCR3 suppressed the action of eotaxin-1, the event appeared CCR3 dependent. Moreover, we observed that interleukin (IL)-1β induced markedly enhanced eotaxin-1 release from FLS, but TNF-α reduced eotaxin-1 release at 12 and 24 h following incubation. In conclusion, enhanced expression of CCR3 on synovial cells and increased levels of eotaxin-1 in plasma and synovial fluid (SF) of RA indicate that CCR3-mediated mechanisms may play an important role in RA. Blockage of eotaxin-1 provoked CCR3 and MMP-9 expression in FLS by antagonist of CCR3, implicating that anti-CCR3 agents may have therapeutic use for RA.

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Abbreviations

FLS:

Fibroblast-like synoviocyte

MFI:

Mean fluorescence intensity

MMP:

Matrix metalloproteinase

OA:

Osteoarthritis

RA:

Rheumatoid arthritis

SF:

Synovial fluid

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Acknowledgments

This project was sponsored by the grants from the “12th Five-Year” National Science and Technology Supporting Plan (2014BAI07B02); the National Natural Science Foundation of China (Nos. 81172836, 81471592, 81472016); Major Science and Technology Platform for Institution of Higher Education in Liaoning Province (2014168); the National Natural Science Foundation of Liaoning Province (2014022027, 2014022019, 2014410004); Program for Liaoning Innovation Research Team in Universities (LNIRT, LT2013017); Climbing Scholar Project for Institution of Higher Education in Liaoning Province (2013222); Allergic Disease Translational Medicine Research Center of Liaoning Province (2015225016); Liaoning Provincial Engineering Research Center for Diagnosing & Treating Inflammatory Disease (20141093); Clinical Capability Construction Project for Liaoning Provincial Hospitals (LNCCC-A06-2014, LNCCC-D26-2015); and “12th Five-Year” public welfare industry special scientific research project (2015SQ00136).

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    Authors and Affiliations

    1. Allergy and Clinical Immunology Research Centre, The First Affiliated Hospital of Jinzhou Medical University, No. 2, Section 5, Renmin Street, Guta District, Jinzhou, Liaoning, 121001, People’s Republic of China

      Xin Liu, Huiyun Zhang, Wenjiao Zheng, Yanan Xu, Junling Wang, Wei Gao & Shaoheng He

    2. Department of Rheumatology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215006, China

      Xin Chang

    3. Department of Orthopaedics, Affiliated Hospital of Nanjing University of TCM, Nanjing, Jiangsu, 210029, China

      Jirong Shen

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    1. Xin Liu
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    Correspondence to Huiyun Zhang or Shaoheng He.

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    All samples obtained were with informed consent from each patient. All experiments were approved by the Ethical Committee of The First Affiliated Hospital of Jinzhou Medical University.

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    The authors declare that they have no conflict of interests.

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    Xin Liu, Huiyun Zhang and Xin Chang contributed equally to this work.

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    Liu, X., Zhang, H., Chang, X. et al. Upregulated expression of CCR3 in rheumatoid arthritis and CCR3-dependent activation of fibroblast-like synoviocytes. Cell Biol Toxicol 33, 15–26 (2017). https://doi.org/10.1007/s10565-016-9356-7

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    • DOI: https://doi.org/10.1007/s10565-016-9356-7

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