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
  • 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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