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SHP2-Triggered Endothelial Cell Activation Fuels Estradiol-Independent Endometrial Sterile Inflammation

文献类型：期刊论文

作者Pan, Jie6,7; Qu, Jiao2,6,7; Fang, Wen6,7; Zhao, Lixin6,7; Zheng, Wei6,7; Zhai, Linhui1; Tan, Minjia1; Xu, Qiang6,7; Du, Qianming4,5; Lv, Wen3
刊名ADVANCED SCIENCE
出版日期2024-09-05
页码22
关键词cell-cell interaction endometrial hyperplasia endothelial cell activation SHP2-RIPK1-AP-1 axis sterile inflammation
DOI10.1002/advs.202403038
通讯作者Du, Qianming(duqianming@njmu.edu.cn) ; Lv, Wen(lvwen@zjsltdyy.wecom.work) ; Sun, Yang(yangsun@nju.edu.cn)
英文摘要Sterile inflammation occurs in various chronic diseases due to many nonmicrobe factors. Examples include endometrial hyperplasia (EH), endometriosis, endometrial cancer, and breast cancer, which are all sterile inflammation diseases induced by estrogen imbalances. However, how estrogen-induced sterile inflammation regulates EH remains unclear. Here, a single-cell RNA-Seq is used to show that SHP2 upregulation in endometrial endothelial cells promotes their inflammatory activation and subsequent transendothelial macrophage migration. Independent of the initial estrogen stimulation, IL1 beta and TNF alpha from macrophages then create a feedforward loop that enhances endothelial cell activation and IGF1 secretion. This endothelial cell-macrophage interaction sustains sterile endometrial inflammation and facilitates epithelial cell proliferation, even after estradiol withdrawal. The bulk RNA-Seq results and phosphoproteomic analysis show that endothelial SHP2 mechanistically enhances RIPK1 activity by dephosphorylating RIPK1Tyr380. This event activates downstream activator protein 1 (AP-1) and instigates the inflammation response. Furthermore, targeting SHP2 using SHP099 (an allosteric inhibitor) or endothelial-specific SHP2 deletion alleviates endothelial cell activation, macrophage infiltration, and EH progression in mice. Collectively, the findings demonstrate that SHP2 mediates the transition of endothelial activation from estradiol-driven acute inflammation to macrophage-amplified chronic inflammation. Targeting sterile inflammation mediated by endothelial cell activation is a promising strategy for nonhormonal intervention in estrogen-related diseases. SHP2 mediates the transition of endothelial activation from estradiol-driven acute inflammation to macrophage-amplified chronic inflammation. Activated endothelial cells interact with macrophages and epithelial cells to generate and sustain endometrial sterile inflammation, thus promoting endometrial hyperplasia by IGF1. Endothelial SHP2 mechanistically leads to the inflammatory activation of the endothelial cell through activating RIPK1-AP-1 axis after primary estrogen stimulation. image
WOS关键词HYPERPLASIA ; CANCER ; RECEPTOR ; EXPRESSION ; ORGANOIDS ; ESTROGEN ; PROMOTES ; REVEALS ; ATYPIA ; BREAST
资助项目National Key Research and Development Plan ; National Natural Science Foundation of China[82374113] ; National Natural Science Foundation of China[82172558] ; National Natural Science Foundation of China[82373112] ; National Natural Science Foundation of China[82230116] ; Mountain-Climbing Talents Project of Nanjing, Zhejiang Basic Public Welfare Research Project[LGF22H040016] ; Key Project of Zhejiang Traditional Chinese Medicine Science and Technology Plan[2022ZZ007] ; Zhejiang Medical and Health Science and Technology Project[2022KY125] ; [2022YFC3500202]
WOS研究方向Chemistry ; Science & Technology - Other Topics ; Materials Science
语种英语
WOS记录号WOS:001306062500001
出版者WILEY
源URL[http://119.78.100.183/handle/2S10ELR8/313293]  
专题中国科学院上海药物研究所
通讯作者Du, Qianming; Lv, Wen; Sun, Yang
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
2.Xuzhou Med Univ, Jiangsu Key Lab New Drug Res & Clin Pharm, 209 Tongshan Rd, Xuzhou 221004, Jiangsu, Peoples R China
3.Tongde Hosp Zhejiang Prov, Dept Gynecol, 234 Gucui Rd, Hangzhou 310012, Zhejiang, Peoples R China
4.China Pharmaceut Univ, Sch Basic Med & Clin Pharm, Nanjing 210009, Peoples R China
5.Nanjing Med Univ, Nanjing Hosp 1, Gen Clin Res Ctr, Nanjing 210006, Peoples R China
6.Nanjing Univ, Nanjing Drum Tower Hosp, Sch Life Sci, Affiliated Hosp,Med Sch, 163 Xianlin Ave, Nanjing 210023, Peoples R China
7.Nanjing Univ, State Key Lab Pharmaceut Biotechnol, Sch Life Sci, 163 Xianlin Ave, Nanjing 210023, Peoples R China
推荐引用方式
GB/T 7714		 Pan, Jie,Qu, Jiao,Fang, Wen,et al. SHP2-Triggered Endothelial Cell Activation Fuels Estradiol-Independent Endometrial Sterile Inflammation[J]. ADVANCED SCIENCE,2024:22.
APA Pan, Jie.,Qu, Jiao.,Fang, Wen.,Zhao, Lixin.,Zheng, Wei.,...&Sun, Yang.(2024).SHP2-Triggered Endothelial Cell Activation Fuels Estradiol-Independent Endometrial Sterile Inflammation.ADVANCED SCIENCE,22.
MLA Pan, Jie,et al."SHP2-Triggered Endothelial Cell Activation Fuels Estradiol-Independent Endometrial Sterile Inflammation".ADVANCED SCIENCE (2024):22.

入库方式： OAI收割

来源：上海药物研究所

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