Recruitment of immune cells to the site of inflammation by the chemokine CCL1 is important in the pathology of inflammatory diseases. Here, we examined the role of CCL1 in pulmonary fibrosis (PF). Bronchoalveolar lavage fluid from PF mouse models contained high amounts of CCL1, as did lung biopsies from PF patients. Immunofluorescence analyses revealed that 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 spectrometry analyses of CCL1 complexes identified AMFR as a CCL1 receptor, and deletion of Amfr impaired fibroblast activation. Mechanistically, CCL1 binding triggered ubiquitination of the ERK inhibitor Spry1 by AMFR, thus activating Ras-mediated profibrotic protein synthesis. Antibody blockade of CCL1 ameliorated PF pathology, supporting the therapeutic potential of targeting this pathway for treating fibroproliferative lung diseases.

趋化因子 CCL1 将免疫细胞募集到炎症部位在炎症性疾病的病理学中很重要。在这里，我们检查了 CCL1 在肺纤维化 (PF) 中的作用。来自 PF 小鼠模型的支气管肺泡灌洗液含有大量的 CCL1，来自 PF 患者的肺活检也是如此。免疫荧光分析显示，肺泡巨噬细胞和 CD4 ⁺ T 细胞是 CCL1 的主要产生者，并且这些细胞中Ccl1的靶向缺失减弱了病理学。成纤维细胞中 CCL1 受体Ccr8的缺失限制了响应 CCL1 的迁移，但不限制激活。CCL1 复合物的质谱分析将 AMFR 鉴定为 CCL1 受体，以及Amfr的缺失成纤维细胞活化受损。从机制上讲，CCL1 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 病理学，支持靶向该途径治疗纤维增生性肺病的治疗潜力。