Chemokine receptor CCR2 expression by systemic sclerosis fibroblasts - Evidence for autocrine regulation of myofibroblast differentiation
Chemokine receptor CCR2 expression by systemic sclerosis fibroblasts - Evidence for autocrine regulation of myofibroblast differentiation
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DOI：
10.1002/art.21396
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发表时间：
2005-12-01
影响因子：
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通讯作者：
Denton, CP
中科院分区：
文献类型：
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作者：
Carulli, MT;Ong, VH;Denton, CP
Objective.研究趋化因子受体CCR 2在参与系统性硬化症（SSc）发病机制的关键细胞类型上的表达，并评估通过CCL 2/CCR 2自分泌激活SSc真皮成纤维细胞的潜力。使用免疫组织化学和流式细胞术技术检测了皮肤活检组织和干燥的皮肤成纤维细胞中趋化因子受体的表达。使用特异性配体或受体拮抗剂评估CCR 2 + SSc成纤维细胞系中纤维化标志物表达的自分泌调节。我们发现，在早期弥漫性皮肤SSc（dcSSc）的皮肤活检样本中，CCR 2表达较强，但在晚期dcSSc或局限性皮肤SSc中，CCR 2表达不强。双标记证实了CCL 2/CCR 2在肌成纤维细胞、周细胞、淋巴细胞、巨噬细胞和内皮细胞上的上调。从早期dcSSc组织中取出的真皮成纤维细胞分别在55%和66%的细胞株中表达CCR 2和CXCR 2。在对照成纤维细胞中无表达。CCR 2+成纤维细胞表现出促纤维化表型，α-平滑肌肌动蛋白（α-SMA）、结缔组织生长因子（CTGF）和CCL 2过表达。流式细胞术分析鉴定了表达肌成纤维细胞标志物α-SMA的CCR 2 + SSc成纤维细胞的子集。在这些培养物中，特异性抑制CCL 2或CCR 2可减弱α-SMA的过表达，但对CTGF或纤溶酶原激活物抑制剂1无影响。我们的研究结果表明，CCR 2在已知在疾病中被激活的细胞类型的早期dcSSc中上调，这与SSc发病机制中的关键作用一致。SSc成纤维细胞上的CCR 2表达似乎调节CCL 2和α-SMA的表达。我们的研究结果表明，在早期dcSSc中，通过CCL 2/CCR 2环对关键的促纤维化特性进行潜在的自分泌调节。
Objective. To investigate expression of the chemokine receptor CCR2 on key cell types involved in the pathogenesis of systemic sclerosis (SSc) and to assess the potential for autocrine activation of SSc dermal fibroblasts via CCL2/CCR2.Methods. Chemokine receptor expression in skin biopsy tissues and explanted dermal fibroblasts from a well-characterized cohort of SSc patients was examined using immunohistochemistry and flow cytometry techniques. Autocrine regulation of the expression of fibrotic markers in CCR2+ SSc fibroblast cell lines was assessed using specific ligand or receptor antagonists.Results. We identified strong CCR2 expression in skin biopsy samples of early-stage diffuse cutaneous SSc (dcSSc), but not late-stage dcSSc or limited cutaneous SSc. Double labeling confirmed up-regulation of CCL2/ CCR2 on myofibroblasts, pericytes, lymphocytes, macrophages, and endothelial cells. Explanted dermal fibroblasts from early dcSSc tissues expressed CCR2 and CXCR2 in 55% and 66% of cell strains, respectively. There was no expression in control fibroblasts. CCR2+ fibroblasts demonstrated a profibrotic phenotype, with overexpression of alpha-smooth muscle actin (alpha-SMA), connective tissue growth factor (CTGF), and CCL2. Flow cytometric analysis identified a subset of CCR2+ SSc fibroblasts expressing the myofibroblast marker alpha-SMA. In these cultures, specific inhibition of CCL2 or CCR2 attenuated the overexpression of alpha-SMA, but not CTGF or plasminogen activator inhibitor 1.Conclusion. Our results show that CCR2 is up-regulated in early dcSSc on cell types known to be activated in the disease, which is consistent with a key role in SSc pathogenesis. CCR2 expression on SSc fibroblasts appears to regulate the expression of CCL2 and alpha-SMA. Our findings suggest potential autocrine regulation of key profibrotic properties via a CCL2/ CCR2 loop in early-stage dcSSc.