Haas Christian S, Martinez Rita J, Attia Naweah, Haines G Kenneth, Campbell Phillip L, Koch Alisa E
University of Michigan Medical School, Ann Arbor, MI 48109-0680, USA.
Arthritis Rheum. 2005 Dec;52(12):3718-30. doi: 10.1002/art.21476.
Chemokine receptors mediate leukocyte migration into inflamed rheumatoid arthritis (RA) synovial tissue (ST). Knowledge of their distribution is crucial for understanding the evolution of the inflammatory process. In this study, we used rat adjuvant-induced arthritis (AIA), a model for RA, to define the temporospatial expression of chemokine receptors.
ST from rats with AIA was immunostained, the percentage of cells expressing each receptor was determined, and findings were correlated with levels of inflammation. Chemokine receptor expression was evaluated on rat macrophages in vitro.
CCR1, a receptor for macrophage inflammatory protein 1alpha (MIP-1alpha)/CCL3 and RANTES/CCL5, exhibited high constitutive expression on macrophages in AIA. CCR5, binding MIP-1alpha/CCL3 and RANTES/CCL5, was up-regulated on ST macrophages during the course of AIA, correlating with macrophage expression of CCR2, a receptor for monocyte chemoattractant protein 1/CCL2. Endothelial cell (EC) CCR2 was down-regulated as arthritis progressed, inversely correlating with inflammation. CCR3, another RANTES/CCL5 receptor, was constitutively high on macrophages in vivo and in vitro, with down-regulation during AIA. CXCR4, a receptor for stromal cell-derived factor 1/CXCL12), was prominently up-regulated on ECs, preceding the peak of inflammation.
These findings show that 1) constitutive expression of CCR1 on macrophages remains high during AIA; 2) CCR2 and CCR3 may play a role in initial recruitment of leukocytes to ST in AIA; 3) macrophage expression of CCR2 and CCR5 may be important for sustaining inflammatory changes; and 4) EC CXCR4 may be a harbinger of inflammatory changes. Our results may help guide chemokine receptor blockade-targeting treatment strategies in inflammatory arthritis.
趋化因子受体介导白细胞迁移至类风湿性关节炎（RA）炎症滑膜组织（ST）中。了解它们的分布对于理解炎症过程的演变至关重要。在本研究中，我们使用大鼠佐剂性关节炎（AIA）这一RA模型来确定趋化因子受体的时空表达。
对患AIA大鼠的ST进行免疫染色，确定表达各受体的细胞百分比，并将结果与炎症水平相关联。在体外对大鼠巨噬细胞的趋化因子受体表达进行评估。
CCR1是巨噬细胞炎性蛋白1α（MIP-1α）/CCL3和调节激活正常T细胞表达和分泌因子（RANTES）/CCL5的受体，在AIA大鼠的巨噬细胞上呈现高组成性表达。结合MIP-1α/CCL3和RANTES/CCL5的CCR5在AIA病程中ST巨噬细胞上上调，与CCR2（单核细胞趋化蛋白1/CCL2的受体）在巨噬细胞上的表达相关。随着关节炎进展，内皮细胞（EC）CCR2下调，与炎症呈负相关。CCR3是另一种RANTES/CCL5受体，在体内和体外巨噬细胞上均呈组成性高表达，在AIA期间下调。CXCR4是基质细胞衍生因子1/CXCL12的受体，在炎症高峰前在EC上显著上调。
这些发现表明：1）在AIA期间，CCR1在巨噬细胞上的组成性表达保持高水平；2）CCR2和CCR3可能在AIA中白细胞向ST的初始募集过程中发挥作用；3）CCR2和CCR5在巨噬细胞上的表达可能对维持炎症变化很重要；4）EC CXCR4可能是炎症变化的先兆。我们的结果可能有助于指导针对炎症性关节炎的趋化因子受体阻断治疗策略。
