Journal
CELLULAR AND MOLECULAR LIFE SCIENCES
Volume 77, Issue 7, Pages 1387-1399Publisher
SPRINGER BASEL AG
DOI: 10.1007/s00018-019-03235-w
Keywords
Rheumatoid arthritis; M1 macrophages; Th17 cells; Osteoclastogenesis; CCL21; CCR7
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Funding
- Foundation for the National Institutes of Health [AR056099, AR065778] Funding Source: Medline
- NIAID NIH HHS [R41 AI147697, R01 AI167155] Funding Source: Medline
- NIAMS NIH HHS [R03 AR065778, R03 AR056099] Funding Source: Medline
- U.S. Department of Veterans Affairs [1I01BX002286] Funding Source: Medline
- BLRD VA [I01 BX002286] Funding Source: Medline
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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 IFN gamma 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 naive 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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