STING Contributes to Pulmonary Hypertension by Targeting IFN and BMPR2 Signaling through Regulating of F2RL3

Deng, Lin1,2; Cao, Chengrui1; Cai, Zongye3; Wang, Ziping1; Leng, Bin4,5; Chen, Zhen1; Kong, Fanhao1; Zhou, Zhiyue1; He, Jun1; Nie, Xiaowei6; Bian, Jin-Song1

2024-09-01

10.1165/rcmb.2023-0308OC

AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY   影响因子和分区

1044-1549

1535-4989

Pulmonary hypertension (PH) is an incurable disease characterized by pulmonary vascular remodeling. Endothelial injury and inflammation are the key triggers of disease initiation. Recent findings suggest that STING (stimulator of IFN genes) activation plays a critical role in endothelial dysfunction and IFN signaling. Here, we investigated the involvement of STING in the pathogenesis of PH. Patients with PH and rodent PH model samples, a Sugen 5416/hypoxia PH model, and pulmonary artery endothelial cells (PAECs) were used to evaluate the hypothesis. We found that the cyclic guanosine monophosphate-AMP synthase-STING signaling pathway was activated in lung tissues from rodent PH models and patients with PH and in TNF-alpha-induced PAECs in vitro. Specifically, STING expression was significantly elevated in the endothelial cells in PH disease settings. In the Sugen 5416/hypoxia mouse model, genetic knockout or pharmacological inhibition of STING prevented the progression of PH. Functionally, knockdown of STING reduced the proliferation and migration of PAECs. Mechanistically, STING transcriptionally regulates its binding partner F2RL3 (F2R-like thrombin or trypsin receptor 3) through the STING-NF-kappa B axis, which activated IFN signaling and repressed BMPR2 (bone morphogenetic protein receptor 2) signaling both in vitro and in vivo. Further analysis revealed that F2RL3 expression was increased in PH settings and identified negative feedback regulation of F2RL3/BMPR2 signaling. Accordingly, a positive correlation of expression amounts between STING and F2RL3/IFN-stimulated genes was observed in vivo. Our findings suggest that STING activation in PAECs plays a critical role in the pathobiology of PH. Targeting STING may be a promising therapeutic strategy for preventing the development of PH.

pulmonary hypertension STING IFN F2RL3 BMPR2

SCI

英语

第一 ; 通讯

National Natural Science Foundation of China["82100060","82170064","82241021"] ; Shenzhen Excellent Science and Technology Innovation Talent Development Programme[RCJC20210706091946002] ; Shenzhen Science and Technology Program[JSGGZD20220822095200001] ; Guangdong Basic and Applied Basic Research Foundation[2022A1515012445] ; China Postdoctoral Science Foundation["2020M680079","2021T140598"]

Biochemistry & Molecular Biology ; Cell Biology ; Respiratory System

Biochemistry & Molecular Biology ; Cell Biology ; Respiratory System

WOS:001322578200012

AMER THORACIC SOC

Web of Science

1.Southern Univ Sci & Technol, Hong Kong Univ Vasc Homeostasis & Dis, Sch Med, Dept Pharmacol,Joint Lab Guangdong, Shenzhen, Peoples R China
2.Sun Yat sen Univ, Affiliated Hosp 8, Dept Cardiol, Shenzhen, Peoples R China
3.Zhejiang Univ, Affiliated Hosp 2, Sch Med, Dept Cardiol, Hangzhou, Peoples R China
4.Natl Univ Singapore, Dept Food Sci & Technol, Singapore, Singapore
5.Natl Univ Singapore, Suzhou Res Inst, Suzhou, Peoples R China
6.Southern Univ Sci & Technol, Shenzhen Peoples Hosp, Affiliated Hosp 1, Shenzhen Key Lab Resp Dis, Shenzhen, Peoples R China

Deng, Lin,Cao, Chengrui,Cai, Zongye,et al. STING Contributes to Pulmonary Hypertension by Targeting IFN and BMPR2 Signaling through Regulating of F2RL3[J]. AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY,2024,71(3).

Deng, Lin.,Cao, Chengrui.,Cai, Zongye.,Wang, Ziping.,Leng, Bin.,...&Bian, Jin-Song.(2024).STING Contributes to Pulmonary Hypertension by Targeting IFN and BMPR2 Signaling through Regulating of F2RL3.AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY,71(3).

Deng, Lin,et al."STING Contributes to Pulmonary Hypertension by Targeting IFN and BMPR2 Signaling through Regulating of F2RL3".AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY 71.3(2024).