Abstract
In rheumatoid arthritis (RA), synovial tissue abundantly expresses CCL21, a chemokine strongly associated with RA susceptibility. In this study, we aimed to characterize the functional significance of CCL21/CCR7 signaling in different phases of RA pathogenesis. We determined that CCR7 is a hallmark of RA M1 synovial fluid (SF) macrophages, and its expression in RA monocytes and in vitro differentiated macrophages is closely associated with disease activity score (DAS28). In early stages of RA, monocytes infiltrate the synovial tissue. However, blockade of SF CCL21 or CCR7 prevents RA SF-mediated monocyte migration. CCR7 expression in the newly migrated macrophages can be accentuated by LPS and IFNγ and suppressed by IL-4 treatment. We also uncovered that CCL21 stimulation increases the number of M1-polarized macrophages (CD14+CD86+), resulting in elevated transcription of IL-6 and IL-23. These CCL21-induced M1 cytokines differentiate naïve T cells to Th17 cells, without affecting Th1 cell polarization. In the erosive stages of disease, CCL21 potentiates RA osteoclastogenesis through M1-driven Th17 polarization. Disruption of this intricate crosstalk, by blocking IL-6, IL-23, or IL-17 function, impairs the osteoclastogenic capacity of CCL21. Consistent with our in vitro findings, we establish that arthritis mediated by CCL21 expands the joint inflammation to bone erosion by connecting the differentiation of M1 macrophages with Th17 cells. Disease progression is further exacerbated by CCL21-induced neovascularization. We conclude that CCL21 is an attractive novel target for RA therapy, as blockade of its function may abrogate erosive arthritis modulated by M1 macrophages and Th17 cell crosstalk.
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Abbreviations
- Ab:
-
Antibody
- Ad-CCL21:
-
Recombinant adenovirus facilitating CCL21 expression
- Ad-Ctrl:
-
Empty adenoviral vector
- Arg1:
-
Arginase 1
- BM:
-
Bone marrow
- CIA:
-
Collagen-induced arthritis
- DAS28:
-
Disease activity score (determined by 28 joint count)
- DMARD:
-
Disease-modifying anti-rheumatic drugs
- GWAS:
-
Genome-wide association studies
- HPF:
-
High-power field
- IL:
-
Interleukin
- NL:
-
Healthy donor
- PB:
-
Peripheral blood
- PBMC:
-
Peripheral blood mononuclear cells
- RA:
-
Rheumatoid arthritis
- SF:
-
Synovial fluid
- ST:
-
Synovial tissue
- TRAP:
-
Tartrate-resistant acid phosphatase
- VEGF:
-
Vascular endothelial growth factor
- WB:
-
Western blot
- WT:
-
Wild type
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Acknowledgements
This work was supported in part by awards from the Department of Veteran’s Affairs MERIT Award 1I01BX002286, the National Institutes of Health AR056099 and AR065778 and the National Psoriasis Foundation (NPF). We also want to thank the clinical staff at the Division of Rheumatology at UIC, who have aided us to inform and involve patients in our studies and enable us to pursue clinically relevant, translational research.
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Van Raemdonck, K., Umar, S., Palasiewicz, K. et al. CCL21/CCR7 signaling in macrophages promotes joint inflammation and Th17-mediated osteoclast formation in rheumatoid arthritis. Cell. Mol. Life Sci. 77, 1387–1399 (2020). https://doi.org/10.1007/s00018-019-03235-w
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DOI: https://doi.org/10.1007/s00018-019-03235-w