Women's Guild Lung Institute, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, University of California, Davis, Sacramento, California, USA.
JCI Insight. 2021 Jun 8;6(11):141061. doi: 10.1172/jci.insight.141061.
Idiopathic pulmonary fibrosis (IPF) is characterized by aberrant repair that diminishes lung function via mechanisms that remain poorly understood. CC chemokine receptor (CCR10) and its ligand CCL28 were both elevated in IPF compared with normal donors. CCR10 was highly expressed by various cells from IPF lungs, most notably stage-specific embryonic antigen-4-positive mesenchymal progenitor cells (MPCs). In vitro, CCL28 promoted the proliferation of CCR10+ MPCs while CRISPR/Cas9-mediated targeting of CCR10 resulted in the death of MPCs. Following the intravenous injection of various cells from IPF lungs into immunodeficient (NOD/SCID-γ, NSG) mice, human CCR10+ cells initiated and maintained fibrosis in NSG mice. Eph receptor A3 (EphA3) was among the highest expressed receptor tyrosine kinases detected on IPF CCR10+ cells. Ifabotuzumab-targeted killing of EphA3+ cells significantly reduced the numbers of CCR10+ cells and ameliorated pulmonary fibrosis in humanized NSG mice. Thus, human CCR10+ cells promote pulmonary fibrosis, and EphA3 mAb-directed elimination of these cells inhibits lung fibrosis.
特发性肺纤维化 (IPF) 的特征是异常修复，通过仍未充分了解的机制导致肺功能下降。与正常供体相比，CC 趋化因子受体 (CCR10) 及其配体 CCL28 在 IPF 中均升高。CCR10 在来自 IPF 肺的各种细胞中高度表达，尤其是阶段特异性胚胎抗原-4 阳性间充质祖细胞 (MPC)。在体外，CCL28 促进 CCR10+MPC 的增殖，而 CRISPR/Cas9 介导的 CCR10 靶向导致 MPC 死亡。在将来自 IPF 肺的各种细胞静脉注射到免疫缺陷 (NOD/SCID-γ，NSG) 小鼠中后，人 CCR10+细胞在 NSG 小鼠中引发并维持纤维化。Eph 受体 A3 (EphA3) 是在 IPF CCR10+细胞上检测到的表达最高的受体酪氨酸激酶之一。针对 EphA3+细胞的 Ifabotuzumab 靶向杀伤显著减少了 CCR10+细胞的数量，并改善了人源化 NSG 小鼠的肺纤维化。因此，人 CCR10+细胞促进肺纤维化，而 EphA3 mAb 定向消除这些细胞可抑制肺纤维化。
