2. Academic Validation
  3. EP3 enhances adhesion and cytotoxicity of NK cells toward hepatic stellate cells in a murine liver fibrosis model

EP3 enhances adhesion and cytotoxicity of NK cells toward hepatic stellate cells in a murine liver fibrosis model

  • J Exp Med. 2022 May 2;219(5):e20212414. doi: 10.1084/jem.20212414.
Xixi Tao  # 1,  Rui Zhang  # 1,  Ronglu Du  # 1,  Tingting Yu  # 1,  Hui Yang 2,  Jiwen Li 2,  Yuhong Wang 1,  Qian Liu 1,  Shengkai Zuo 1,  Xi Wang 3,  Michael Lazarus 4,  Lu Zhou 2,  Bangmao Wang 2,  Ying Yu 1,  Yujun Shen 1
Affiliations

Affiliations

  • 1 Department of Pharmacology, Tianjin Key Laboratory of Inflammatory Biology, Center for Cardiovascular Diseases, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
  • 2 Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China.
  • 3 Department of Immunology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.
  • 4 International Institute for Integrative Sleep Medicine, University of Tsukuba, Tsukuba City, Ibaraki, Japan.
  • # Contributed equally.
PMID: 35420633 DOI: 10.1084/jem.20212414
Abstract

Natural killer (NK) cells exhibit antifibrotic properties in liver fibrosis (LF) by suppressing activated hepatic stellate cell (HSC) populations. Prostaglandin E2 (PGE2) plays a dual role in innate and adaptive immunity. Here, we found that E-prostanoid 3 receptor (EP3) was markedly downregulated in NK cells from liver fibrosis mice and patients with liver cirrhosis. NK cell-specific deletion of EP3 aggravated hepatic fibrogenesis in mouse models of LF. Loss of EP3 selectively reduced the cytotoxicity of the CD27+CD11b+ double positive (DP) NK subset against activated HSCs. Mechanistically, deletion of EP3 impaired the adhesion and cytotoxicity of DP NK cells toward HSCs through modulation of Itga4-VCAM1 binding. EP3 upregulated Itga4 expression in NK cells through promoting Spic nuclear translocation via PKC-mediated phosphorylation of Spic at T191. Activation of EP3 by sulprostone alleviated CCL4-induced liver fibrosis in mice. Thus, EP3 is required for adhesion and cytotoxicity of NK cells toward HSCs and may serve as a therapeutic target for the management of LF.

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