Secondary lymphoid tissue chemokine (SLC/CCL21)/CCR7 signaling regulates fibrocytes in renal fibrosis
Secondary lymphoid tissue chemokine (SLC/CCL21)/CCR7 signaling regulates fibrocytes in renal fibrosis
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DOI：
10.1073/pnas.0511200103
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发表时间：
2006-09-19
影响因子：
11.1
通讯作者：
Kaneko, Shuichi
中科院分区：
文献类型：
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作者：
Sakai, Norihiko;Wada, Takashi;Kaneko, Shuichi
纤维细胞是一种独特的血源性细胞群，它们具有白细胞和间充质细胞的标记。我们假设 CCR7 阳性纤维细胞响应次级淋巴组织趋化因子 (SLC/CCL21) 迁移到肾脏中，并导致肾纤维化。为了研究这一假设，小鼠单侧输尿管梗阻诱导肾纤维化。相当数量的 CD45 和 I 型胶原 (Coll) 双阳性或 CD34 和 Coll 双阳性的纤维细胞浸润间质，在第 7 天达到峰值。大多数纤维细胞 CCR7 阳性，CCL21/CCR7 阻断减少了浸润纤维细胞的数量。间质中也检测到CCL21和MECA79双阳性血管。抗 CCL21 抗体阻断 CCL21/CCR7 信号传导可减少肾纤维化，这一点通过 CCR7 缺失小鼠纤维化的减少以及 Coll 的前 α 1 链和 TGF-β(1) 肾转录物的同时减少证实。阻断 CCL21/CCR7 信号传导后，F4/80 阳性巨噬细胞的数量以及单核细胞趋化蛋白 1 (MCP-1/CCL2) 的肾脏转录物减少。这些发现表明，CCR7 阳性纤维细胞通过 CCL21 阳性血管浸润肾脏，从而促进肾纤维化的发病机制。因此，纤维细胞的 CCL21/CCR7 信号传导可能提供对抗肾纤维化的治疗靶点。
Fibrocytes are a distinct population of bloodborne cells that share markers of leukocytes as well as mesenchymal cells. We hypothesized that CCR7-positive fibrocytes migrate into the kidney in response to secondary lymphoid tissue chemokine (SLC/CCL21) and contribute to renal fibrosis. To investigate this hypothesis, renal fibrosis was induced by unilateral ureteral obstruction in mice. A considerable number of fibrocytes dual-positive for CD45 and type I collagen (Coll) or CD34 and Coll infiltrated the interstitium, reaching a peak on day 7. Most fibrocytes were positive for CCR7, and CCL21/CCR7 blockade reduced the number of infiltrating fibrocytes. CCL21 and MECA79 dual-positive vessels were also detected in the interstitium. The blockade of CCL21/CCR7 signaling by anti-CCL21 antibodies reduced renal fibrosis, which was confirmed by a decrease in fibrosis in CCR7-null mice with concomitant reduction in renal transcripts of pro alpha 1 chain of Coll and TGF-beta(1). The number of F4/80-positive macrophages decreased along with renal transcripts of monocyte chemoattractant protein 1 (MCP-1/CCL2) after the blockade of CCL21/CCR7 signaling. These findings suggest that CCR7-positive fibrocytes infiltrate the kidney via CCL21-positive vessels, thereby contributing to the pathogenesis of renal fibrosis. Thus, the CCL21/CCR7 signaling of fibrocytes may provide therapeutic targets for combating renal fibrosis.