Macrophage ferroportin serves as a therapeutic target against bacteria-induced acute lung injury by promoting barrier restoration
Hanbin Wang,
Congli Zeng,
Gan Luo,
Yaqi Sun,
Jue Zhang,
Zhipeng Xu,
Yuqian Guo,
Hui Ye,
Jiali Mao,
Shiyu Chen,
Yan Zhang,
Kai Zhang,
Marcos F. Vidal Melo,
Xiangming Fang
Affiliations
Hanbin Wang
Department of Anesthesiology and Intensive Care, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
Congli Zeng
Department of Anesthesiology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
Gan Luo
Department of Anesthesiology and Intensive Care, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
Yaqi Sun
Department of Anesthesiology and Intensive Care, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
Jue Zhang
Department of Anesthesiology and Intensive Care, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
Zhipeng Xu
Department of Anesthesiology and Intensive Care, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
Yuqian Guo
Department of Anesthesiology and Intensive Care, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
Hui Ye
Department of Anesthesiology and Intensive Care, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
Jiali Mao
Department of Anesthesiology and Intensive Care, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
Shiyu Chen
Department of Anesthesiology and Intensive Care, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
Yan Zhang
National Clinical Research Center for Child Health, Children’s Hospital, School of Medicine, Zhejiang University, Hangzhou 310052, China
Kai Zhang
Department of Anesthesiology and Intensive Care, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
Marcos F. Vidal Melo
Department of Anesthesiology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
Xiangming Fang
Department of Anesthesiology and Intensive Care, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China; Corresponding author
Summary: Acute respiratory distress syndrome (ARDS) is a common lung disorder that involves severe inflammatory damage in the pulmonary barrier, but the underlying mechanisms remain elusive. Here, we demonstrated that pulmonary macrophages originating from ARDS patients and mice caused by bacteria were characterized by increased expression of ferroportin (FPN). Specifically deleting FPN in myeloid cells conferred significant resistance to bacterial infection with improved survival by decreasing extracellular bacterial growth and preserving pulmonary barrier integrity in mice. Mechanistically, macrophage FPN deficiency not only limited the availability of iron to bacteria, but also promoted tissue restoration via growth factor amphiregulin, which is regulated by cellular iron-activated Yes-associated protein signaling. Furthermore, pharmacological treatment with C-Hep, the self-assembled N-terminally cholesterylated minihepcidin that functions in the degradation of macrophage FPN, protected against bacteria-induced lung injury. Therefore, therapeutic strategies targeting the hepcidin-FPN axis in macrophages may be promising for the clinical treatment of acute lung injury.
