Stromal Cell-Derived Factor-1-CXC Chemokine Receptor 4 Interactions Play a Central Role in CD4+ T Cell Accumulation in Rheumatoid Arthritis Synovium

Abstract

Rheumatoid arthritis (RA) is characterized by the accumulation of CD4+ memory T cells in the inflamed synovium. To address the mechanism, we analyzed chemokine receptor expression and found that the frequency of CXC chemokine receptor (CXCR)4 expressing synovial tissue CD4+ memory T cells was significantly elevated. CXCR4 expression could be enhanced by IL-15, whereas stromal cell-derived factor (SDF)-1, the ligand of CXCR4, was expressed in the RA synovium and could be increased by CD40 stimulation. SDF-1 stimulated migration of rheumatoid synovial T cells and also inhibited activation-induced apoptosis of T cells. These results indicate that SDF-1-CXCR4 interactions play important roles in CD4+ memory T cell accumulation in the RA synovium, and emphasize the role of stromal cells in regulating rheumatoid inflammation.

Interleukin‐18 induces angiogenic factors in rheumatoid arthritis synovial tissue fibroblasts via distinct signaling pathways

“…Nanki and colleagues demonstrated that CD40 ligation induces increased expression of SDF-1␣/CXCL12 in RA ST fibroblasts (9). Conversely, Hitchon et al reported that hypoxiainducible factor 1␣ (HIF-1␣) and VEGF enhanced expression of SDF-1␣/CXCL12 mRNA in RA ST fibroblasts, although they did not demonstrate induction of SDF-1␣/CXCL12 protein by TNF␣ or IL-1␤ in RA ST fibroblasts (38).…”

“…SDF-1␣/CXCL12 plays an important role in the pathogenesis of RA, in that it mediates homing of leukocytes to RA ST and causes the release of matrix metalloproteinase 3 (MMP-3) by chondrocytes (8,9). SDF-1␣/CXCL12 increases the migration and survival of B and T cells in vitro, and exogenous SDF-1␣/CXCL12 increases monocyte migration in a dosedependent manner in a SCID/RA ST chimera model (9,10). Moreover, an antagonist of CXCR4 (a receptor for SDF-1␣/CXCL12) ameliorates arthritis in murine CIA (11).…”

Amplification of the synovial inflammatory response through activation of mitogen‐activated protein kinases and nuclear factor κB using ligation of CD40 on CD14+ synovial cells from patients with rheumatoid arthritis

“…Other investigators have also demonstrated that CD68ϩ synovial macrophage lineage cells as well as fibroblast-like synoviocytes (FLS) express CD40 (8,9). The ligation of CD40 augments the production of IL-12 in synovial cells and synovial fluid macrophages from RA patients (10,11) and enhances the expression of CD54, CD106, IL-6 (12), stromal cell-derived factor 1 (13), and vascular endothelial cell growth factor (14). In vivo, treatment with a monoclonal antibody (mAb) against CD154 prevents the development of type II collagen-induced arthritis in mice (15).…”

Expression of chemokines and gelatinase B in sympathetic ophthalmia

“…31 Additionally, the administration of anti-SDF-1 antibody prevented the development of autoantibodies, nephritis, and death in a murine model of lupus. 32 The expression of SDF-1, which is capable of inducing lymphocyte migration to lymphoid organs, 33 is increased in chronically inflamed tissues such as rheumatoid arthritis synovium, [34][35][36] and the thyroid gland from patients with autoimmune thyroid disease. 22 On the basis of a wide expression of SDF-1 in rheumatoid arthritis synovium, several studies demonstrated that SDF-1 and its receptor CXCR4 are involved in CD4 þ and CD8 þ T-cell 34,35 and CD68 þ monocyte/macrophage 36 migration to and retention in rheumatoid arthritis synovium.…”

“…32 The expression of SDF-1, which is capable of inducing lymphocyte migration to lymphoid organs, 33 is increased in chronically inflamed tissues such as rheumatoid arthritis synovium, [34][35][36] and the thyroid gland from patients with autoimmune thyroid disease. 22 On the basis of a wide expression of SDF-1 in rheumatoid arthritis synovium, several studies demonstrated that SDF-1 and its receptor CXCR4 are involved in CD4 þ and CD8 þ T-cell 34,35 and CD68 þ monocyte/macrophage 36 migration to and retention in rheumatoid arthritis synovium. The expression of SDF-1 by monocytes/macrophages and endothelial cells in SO agrees with immunolocalization studies in rheumatoid arthritis synovium, 36 and suggests a pathogenic role of SDF-1 in the recruitment of leucocytes including B lymphocytes into the eye.…”