Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, China.
Department of Anatomy, Zhejiang University School of Medicine, Hangzhou, 310058, China.
Signal Transduct Target Ther. 2021 Feb 28;6(1):91. doi: 10.1038/s41392-021-00482-x.
Eosinophils are terminally differentiated cells derived from hematopoietic stem cells (HSCs) in the bone marrow. Several studies have confirmed the effective roles of eosinophils in asthmatic airway pathogenesis. However, their regulatory functions have not been well elucidated. Here, increased C-C chemokine ligand 6 (CCL6) in asthmatic mice and the human orthologs CCL15 and CCL23 that are highly expressed in asthma patients are described, which are mainly derived from eosinophils. Using Ccl6 knockout mice, further studies revealed CCL6-dependent allergic airway inflammation and committed eosinophilia in the bone marrow following ovalbumin (OVA) challenge and identified a CCL6-CCR1 regulatory axis in hematopoietic stem cells (HSCs). Eosinophil differentiation and airway inflammation were remarkably decreased by the specific CCR1 antagonist BX471. Thus, the study identifies that the CCL6-CCR1 axis is involved in the crosstalk between eosinophils and HSCs during the development of allergic airway inflammation, which also reveals a potential therapeutic strategy for targeting G protein-coupled receptors (GPCRs) for future clinical treatment of asthma.
嗜酸性粒细胞是终末分化细胞，源自骨髓中的造血干细胞（HSCs）。多项研究证实了嗜酸性粒细胞在哮喘气道发病机制中的有效作用。然而，其调节功能尚未得到充分阐明。本文描述了哮喘小鼠和哮喘患者中高表达的人同源物 CCL15 和 CCL23 中嗜酸性粒细胞来源的 C-C 趋化因子配体 6（CCL6）增加，这些趋化因子主要来自嗜酸性粒细胞。使用 Ccl6 敲除小鼠，进一步的研究揭示了 CCL6 依赖性变应原（OVA）挑战后骨髓中的过敏气道炎症和嗜酸性粒细胞的定向分化，并确定了造血干细胞（HSCs）中 CCL6-CCR1 调节轴。特异性 CCR1 拮抗剂 BX471 显著降低了嗜酸性粒细胞分化和气道炎症。因此，该研究确定 CCL6-CCR1 轴参与了过敏气道炎症发展过程中嗜酸性粒细胞和 HSCs 之间的串扰，这也为未来哮喘的临床治疗靶向 G 蛋白偶联受体（GPCR）提供了一种潜在的治疗策略。
