STING inhibitor ameliorates LPS-induced ALI by preventing vascular endothelial cells-mediated immune cells chemotaxis and adhesion

doi:10.1038/s41401-021-00813-2

	STING inhibitor ameliorates LPS-induced ALI by preventing vascular endothelial cells-mediated immune cells chemotaxis and adhesion
	Wu, Bing 1,2; Xu, Meng-meng 1,3; Fan, Chen 1; Feng, Chun-lan 1; Lu, Qiu-kai 1,2; Lu, Hui-min 1,2; Xiang, Cai-gui 1,2; Bai, Fang 1,2; Wang, Hao-yu 1,2; Wu, Yan-wei 1
刊名	ACTA PHARMACOLOGICA SINICA
	2021-12-14
页码	12
关键词	acute lung injury STING vascular endothelial cells inflammatory cytokines chemokines chemotaxis
ISSN号	1671-4083
DOI	10.1038/s41401-021-00813-2
通讯作者	Wu, Yan-wei(wuyanwei@simm.ac.cn) ; Tang, Wei(tangwei@simm.ac.cn)
英文摘要	Acute lung injury (ALI) is a common and devastating clinical disorder featured by excessive inflammatory responses. Stimulator of interferon genes (STING) is an indispensable molecule for regulating inflammation and immune response in multiple diseases, but the role of STING in the ALI pathogenesis is not well elucidated. In this study, we explored the molecular mechanisms of STING in regulating lipopolysaccharide (LPS)-induced lung injury. Mice were pretreated with a STING inhibitor C-176 (15, 30 mg/kg, i.p.) before LPS inhalation to induce ALI. We showed that LPS inhalation significantly increased STING expression in the lung tissues, whereas C-176 pretreatment dose-dependently suppressed the expression of STING, decreased the production of inflammatory cytokines including TNF-alpha, IL-6, IL-12, and IL-1 beta, and restrained the expression of chemokines and adhesion molecule vascular cell adhesion protein-1 (VCAM-1) in the lung tissues. Consistently, in vitro experiments conducted in TNF-alpha-stimulated HMEC-1cells (common and classic vascular endothelial cells) revealed that human STING inhibitor H-151 or STING siRNA downregulated the expression levels of adhesion molecule and chemokines in HMEC-1cells, accompanied by decreased adhesive ability and chemotaxis of immunocytes upon TNF-alpha stimulation. We further revealed that STING inhibitor H-151 or STING knockdown significantly decreased the phosphorylation of transcription factor STAT1, which subsequently influenced its binding to chemokine CCL2 and adhesive molecule VCAM-1 gene promoter. Collectively, STING inhibitor can alleviate LPS-induced ALI in mice by preventing vascular endothelial cells-mediated immune cell chemotaxis and adhesion, suggesting that STING may be a promising therapeutic target for the treatment of ALI.
资助项目	Science & Technology Commission of Shanghai Municipality, China[18431907100] ; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences[SIMM2105KF-11]
WOS关键词	ACUTE LUNG INJURY ; INFLAMMATION ; MACROPHAGES ; MECHANISMS ; KIDNEY
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
出版者	NATURE PUBL GROUP
WOS记录号	WOS:000730083700001
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/299181]
专题	中国科学院上海药物研究所
通讯作者	Wu, Yan-wei; Tang, Wei
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Lab Antiinflammat, Shanghai 201203, Peoples R China 2.Univ Chinese Acad Sci, Sch Pharm, Beijing 100049, Peoples R China 3.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210000, Peoples R China
推荐引用方式 GB/T 7714	Wu, Bing,Xu, Meng-meng,Fan, Chen,et al. STING inhibitor ameliorates LPS-induced ALI by preventing vascular endothelial cells-mediated immune cells chemotaxis and adhesion[J]. ACTA PHARMACOLOGICA SINICA,2021:12.
APA	Wu, Bing.,Xu, Meng-meng.,Fan, Chen.,Feng, Chun-lan.,Lu, Qiu-kai.,...&Tang, Wei.(2021).STING inhibitor ameliorates LPS-induced ALI by preventing vascular endothelial cells-mediated immune cells chemotaxis and adhesion.ACTA PHARMACOLOGICA SINICA,12.
MLA	Wu, Bing,et al."STING inhibitor ameliorates LPS-induced ALI by preventing vascular endothelial cells-mediated immune cells chemotaxis and adhesion".ACTA PHARMACOLOGICA SINICA (2021):12.