Abstract
BackgroundRheumatoid arthritis (RA) is a chronic autoimmune disease characterized by uncontrolled joint inflammation and destruction of bone and cartilage. We previously reported that C-X-C motif chemokine 10 (CXCL10; also called IP-10) has important roles in joint inflammation and bone destruction in arthritis. However, the specific mechanisms by which CXCL10 regulates the recruitment of inflammatory cells and the production of osteoclastogenic cytokines in RA progression are not fully understood.MethodsBone marrow-derived macrophages and CD4+ T cells were isolated from wild-type (WT), Cxcl10–/–, and Cxcr3–/– mice. CXCL10-induced migration was performed using a Boyden chamber, and CXCL10-stimulated production of osteoclastogenic cytokines was measured by quantitative real-time PCR and ELISA. Collagen antibody-induced arthritis (CAIA) was induced by administration of collagen type II antibodies and lipopolysaccharide to the mice. Clinical scores were analyzed and hind paws were collected for high-resolution micro-CT, and histomorphometry. Serum was used to assess bone turnover and levels of osteoclastogenic cytokines.ResultsCXCL10 increased the migration of inflammatory cells through C-X-C chemokine receptor 3 (CXCR3)-mediated, but not toll-like receptor 4 (TLR4)-mediated, ERK activation. Interestingly, both receptors CXCR3 and TLR4 were simultaneously required for CXCL10-stimulated production of osteoclastogenic cytokines in CD4+ T cells. Furthermore, calcineurin-dependent NFATc1 activation was essential for CXCL10-induced RANKL expression. In vivo, F4/80+ macrophages and CD4+ T cells robustly infiltrated into synovium of WT mice with CAIA but were significantly reduced in both Cxcl10–/– and Cxcr3–/– mice. Serum concentrations of osteoclastogenic cytokines and bone destruction were also reduced in the knockout mice, leading to attenuated progression of arthritis.ConclusionThese findings highlight the importance of CXCL10 signaling in the pathogenesis of RA and provide previously unidentified details of the mechanisms by which CXCL10 promotes the development of arthritis.
Highlights
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by uncontrolled joint inflammation and destruction of bone and cartilage
Chemokine receptor 3 (CXCR3)-mediated ERK activation but not toll-like receptor 4 (TLR4) Because C-X-C motif chemokine 10 (CXCL10) has been reported to bind to TLR4 as well as to CXCR3 [13], we first investigated whether TLR4 is involved in CXCL10-induced cell migration
The CXCL10-induced migration of Bone marrow-derived macrophage (BMM) (Fig. 1a and Additional file 1: Figure S2) and CD4+ T cells (Fig. 1b and Additional file 1: Figure S3) was blocked in Cxcr3–/– or si-CXCR3 cells compared with WT or si-Control cells
Summary
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by uncontrolled joint inflammation and destruction of bone and cartilage. We previously reported that C-X-C motif chemokine 10 (CXCL10; called IP-10) has important roles in joint inflammation and bone destruction in arthritis. Osteoclasts, multinucleated bone-resorbing cells, are essential mediators of inflammatory bone erosion and are derived from monocyte/macrophage lineage precursor cells through the action of RANKL, a key factor for RA is a common, chronic inflammatory and systemic autoimmune disease characterized by progressive infiltration of lymphocytes and macrophages into synovium, leading to persistent synovial inflammation and destruction of bone and cartilage [3]. The hyperplastic synovial pannus in RA produces proinflammatory cytokines, chemokines, and proteases and subsequently invades and destroys bone and cartilage [10, 11]. Infiltration of inflammatory cells into the synovium is an essential step for the progression of RA
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