Endothelial Shp2 deficiency controls alternative activation of macrophage preventing radiation-induced lung injury through notch signaling

Pan Liu; Yiqing Li; Mengyao Li; Hui Zhou; Huilun Zhang; Yuefei Zhang; Jiaqi Xu; Yun Xu; Jie Zhang; Bing Xia; Hongqiang Cheng; Yuehai Ke; Xue Zhang

doi:10.1016/j.isci.2022.103867

Endothelial Shp2 deficiency controls alternative activation of macrophage preventing radiation-induced lung injury through notch signaling

iScience. 2022 Feb 5;25(3):103867. doi: 10.1016/j.isci.2022.103867. eCollection 2022 Mar 18.

Authors

Pan Liu^{1

2}, Yiqing Li¹, Mengyao Li^{1

3}, Hui Zhou¹, Huilun Zhang¹, Yuefei Zhang^{1

4}, Jiaqi Xu⁵, Yun Xu^{1

6}, Jie Zhang⁷, Bing Xia⁸, Hongqiang Cheng⁹, Yuehai Ke¹, Xue Zhang¹

Affiliations

¹ Department of Pathology and Pathophysiology, and Department of Respiratory Medicine at Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
² Department of Pathology, Institute of Cancer Research and Basic Medical Sciences of Chinese Academy of Sciences, Cancer Hospital of University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, China.
³ Department of Pathology, Shaoxing People's Hospital, Shaoxing, Zhejiang 312000, China.
⁴ School of Life Sciences, Westlake University, Hangzhou, Zhejiang 310024, China.
⁵ Department of Pathology at Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, China.
⁶ The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang 322000, China.
⁷ Department of Pathology and Pathophysiology, and Department of Cardiology at Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
⁸ Department of Thoracic Oncology, Affiliated Hangzhou Cancer Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310002, China.
⁹ Department of Urology at Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, China.

Abstract

Radiation-induced lung injury is a common late side effect of thoracic radiotherapy. Endothelial dysfunction following leukocytes infiltration is a prominent feature in this process. Here, we established a clinical-mimicking mouse model of radiation-induced lung injury and found the activity of phosphatase Shp2 was elevated in endothelium after injury. Endothelium-specific Shp2 deletion mice showed relieved collagen deposition along with disrupted radiation-induced Jag1 expression in the endothelium. Furthermore, endothelium-derived Jag1 activated the alternative activation of macrophages in vitro and in vivo by paracrine Notch signaling. Consistently, the Notch pathway was significantly activated by chest irradiation in the peripheral blood leukocytes of patients with cancer. Collectively, our work demonstrates that Shp2 participates in the radiation-induced endothelial dysfunction and subsequently inflammatory microenvironment producing during radiation-induced lung injury. Our findings indicate Shp2 as a potential target for radiation-induced lung injury and provide another way for endothelium to participate in the pathological process of radiation-induced lung injury.

Keywords: Biological sciences; Immunology; Molecular biology; Transcriptomics.