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研究揭示趋化因子CCL1促进肺纤维化机制
作者:小柯机器人 发布时间:2021/8/22 10:33:40

中南大学Zhuo-wei Hu、Yang Xiao等研究人员合作发现,趋化因子CCL1触发AMFR-SPRY1通路,从而促进肺成纤维细胞向肌成纤维细胞分化,并推动肺纤维化的发展。相关论文于2021年8月17日在线发表在《免疫》杂志上。

研究人员揭示了CCL1在肺纤维化(PF)中的作用。PF小鼠模型的支气管肺泡灌洗液含有大量的CCL1,PF患者的肺部活检也是如此。免疫荧光分析显示,肺泡巨噬细胞和CD4+T细胞是CCL1的主要生产者,有针对性地敲除这些细胞中的CCL1会减弱病变。敲除成纤维细胞中的CCL1受体Ccr8限制了迁移,但不限制对CCL1的激活。CCL1复合物的质谱分析确定了AMFR是CCL1的受体,而Amfr的缺失损害了成纤维细胞的激活。从机制上讲,CCL1的结合触发了AMFR对ERK抑制剂Spry1的泛素化,从而激活了Ras介导的促纤维化蛋白合成。CCL1的抗体阻断改善了PF的病理状态,表明靶向该途径具有治疗纤维增生性肺部疾病的潜力。

据悉,趋化因子CCL1招募免疫细胞到炎症部位在炎症性疾病的病理中很重要。

附:英文原文

Title: The chemokine CCL1 triggers an AMFR-SPRY1 pathway that promotes differentiation of lung fibroblasts into myofibroblasts and drives pulmonary fibrosis

Author: Shan-shan Liu, Chang Liu, Xiao-xi Lv, Bing Cui, Jun Yan, Yun-xuan Li, Ke Li, Fang Hua, Xiao-wei Zhang, Jiao-jiao Yu, Jin-mei Yu, Feng Wang, Shuang Shang, Ping-ping Li, Zhi-guang Zhou, Yang Xiao, Zhuo-wei Hu

Issue&Volume: 2021-08-17

Abstract: Recruitment of immune cells to the site of inflammation by the chemokine CCL1 is importantin the pathology of inflammatory diseases. Here, we examined the role of CCL1 in pulmonaryfibrosis (PF). Bronchoalveolar lavage fluid from PF mouse models contained high amountsof CCL1, as did lung biopsies from PF patients. Immunofluorescence analyses revealedthat alveolar macrophages and CD4+ T cells were major producers of CCL1 and targeted deletion of Ccl1 in these cells blunted pathology. Deletion of the CCL1 receptor Ccr8 in fibroblasts limited migration, but not activation, in response to CCL1. Mass spectrometryanalyses of CCL1 complexes identified AMFR as a CCL1 receptor, and deletion of Amfr impaired fibroblast activation. Mechanistically, CCL1 binding triggered ubiquitinationof the ERK inhibitor Spry1 by AMFR, thus activating Ras-mediated profibrotic proteinsynthesis. Antibody blockade of CCL1 ameliorated PF pathology, supporting the therapeuticpotential of targeting this pathway for treating fibroproliferative lung diseases.

DOI: 10.1016/j.immuni.2021.06.008

Source: https://www.cell.com/immunity/fulltext/S1074-7613(21)00252-1

期刊信息

Immunity:《免疫》,创刊于1994年。隶属于细胞出版社,最新IF:21.522
官方网址:https://www.cell.com/immunity/home
投稿链接:https://www.editorialmanager.com/immunity/default.aspx