Journal Article

CCL21/CCR7 signaling in macrophages promotes joint inflammation and Th17-mediated osteoclast formation in rheumatoid arthritis

Chang, Huan J., Volkov, Suncica, Volin, Michael V., Umar, Sadiq, Palasiewicz, Karol, Sweiss, Nadera, Shahrara, Shiva, Zanotti, Brian, Arami, Shiva, Van Raemdonck, Katrien

2020

Overview

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.

• Publisher: Springer International Publishing,Springer Nature B.V
• Subject: angiogenesis / Animals / Arthritis / Arthritis, Rheumatoid - blood / Arthritis, Rheumatoid - immunology / Arthritis, Rheumatoid - pathology / Autoimmune diseases / Biochemistry / Biocompatibility / Biomarkers - metabolism / Biomedical and Life Sciences / Biomedical materials / Biomedicine / bone formation / CC chemokine receptors / CCL21 protein / CCR7 protein / CD14 antigen / CD86 antigen / Cell Biology / Cell Differentiation / Cell Polarity / Chemokine CCL21 - metabolism / Chemokines / Chemotaxis / Crosstalk / Cytokines / disease progression / Disruption / Female / Helper cells / Humans / Inflammation / Inflammation - pathology / Interleukin 17 / Interleukin 23 / Interleukin 4 / Interleukin 6 / Interleukins - metabolism / Joints (anatomy) / Joints - pathology / Leukocyte migration / Life Sciences / Lipopolysaccharides / Lymphocytes / Lymphocytes T / Macrophages / Macrophages - metabolism / Male / Mice / Mice, Inbred C57BL / Middle Aged / Monocytes / Monocytes - pathology / Myeloid Cells - metabolism / Original Article / Osteoclastogenesis / osteoclasts / Osteoclasts - pathology / Osteogenesis / Pathogenesis / Polarization / Receptors, CCR7 - blood / Receptors, CCR7 - metabolism / Rheumatoid arthritis / Signal Transduction / Signaling / Synovial fluid / Synovial Fluid - metabolism / Th17 Cells - immunology / therapeutics / Transcription / Up-Regulation / Vascularization / γ-Interferon