Basic Study
Copyright ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Mar 7, 2023; 29(9): 1475-1491
Published online Mar 7, 2023. doi: 10.3748/wjg.v29.i9.1475
Adenosine 2A receptor contributes to the facilitation of post-infectious irritable bowel syndrome by γδ T cells via the PKA/CREB/NF-κB signaling pathway
Li-Wei Dong, Yi-Yao Chen, Chao-Chao Chen, Zhi-Chao Ma, Jiao Fu, Bai-Li Huang, Fu-Jin Liu, Dong-Chun Liang, De-Ming Sun, Cheng Lan
Li-Wei Dong, Yi-Yao Chen, Chao-Chao Chen, Zhi-Chao Ma, Jiao Fu, Bai-Li Huang, Fu-Jin Liu, Cheng Lan, Department of Gastroenterology, Hainan General Hospital, Affiliated Hainan Hospital, Hainan Medical University, Haikou 570311, Hainan Province, China
Dong-Chun Liang, De-Ming Sun, Doheny Eye Institute, Department of Ophthalmology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90033, United States
Author contributions: Dong LW, Chen YY, and Chen CC contributed equally to this manuscript and should be as the co-first authors. Lan C, Sun DM, Dong LW, Chen YY, and Chen CC contributed to the conception and design; Lan C, Dong LW, Chen YY, and Chen CC contributed to development of methodology; Dong LW, Chen YY, Chen CC, Ma ZC, Fu J, Huang BL, and Liu FJ contributed to acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.), analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis); Dong LW, Liang DC, and Sun DM contributed to writing, review, and/or revision of the manuscript; Chen YY, Chen CC, and Liang DC contributed to the administrative, technical, or material support (i.e., reporting or organizing data, constructing databases); Lan C supervised the study; all authors have read and approved the final version of the manuscript.
Supported by National Natural Science Foundation of China, No. 81160057, No. 81860102, and No. 82060102; Natural Science Foundation of Hainan Province, High-level Personnel Program, No. 821RC1116; Research Project of Health Industry in Hainan Province, No. 20A200066; and Hainan Provincial Clinical Medical Center.
Institutional animal care and use committee statement: The experimental protocol was approved by the Animal Care and Use Committee of Hainan General Hospital.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Cheng Lan, MD, PhD, Chief Doctor, Professor, Department of Gastroenterology, Hainan General Hospital, Affiliated Hainan Hospital, Hainan Medical University, No. 19 Xiuhua Road, Xiuying District, Haikou 570311, Hainan Province, China. lancheng71@163.com
Received: December 5, 2022
Peer-review started: December 5, 2022
First decision: January 2, 2023
Revised: January 11, 2023
Accepted: February 22, 2023
Article in press: February 22, 2023
Published online: March 7, 2023
ARTICLE HIGHLIGHTS
Research background

Persistent low level of inflammation due to immune dysfunction is regarded as one of the prime pathogenic mechanisms of post-infectious irritable bowel syndrome (PI-IBS). γδ T cells play a key role in innate and adaptive immunity. Adenosine and its receptors expressed on γδ T cells are involved in intestinal inflammation and immune regulation.

Research motivation

To unveil the role of γδ T cells regulated by adenosine 2A receptor (A2AR) in the pathogenesis of PI-IBS.

Research objectives

This study aims to investigate the role of A2AR in γδ T cells and γδ T cells in PI-IBS.

Research methods

A PI-IBS mouse model was established with Trichinella spiralis (T. spiralis) infection. Intestinal A2AR and A2AR in γδ T cells were detected through immunohistochemistry, and inflammatory cytokines were detected through western blot. The role of A2AR on isolated γδ T cells, including γδ T cell proliferation, apoptosis and γδ T cell-mediated cytokine secretion, was assessed in vitro. A2AR expression in γδ T cells was determined by western blot and reverse transcription polymerase chain reaction (RT-PCR). Mice were injected with A2AR agonist or A2AR antagonist and cultured γδ T cells were also reinfused into the animals, and then the above parameters and clinical features were examined again. In addition, alterations in A2AR-related signaling pathway molecules were detected by western blot and RT-PCR.

Research results

The expression levels of ATP and A2AR were increased in PI-IBS mice (P < 0.01), and inhibition of A2AR further enhanced the clinical features of PI-IBS, as reflected by the abdominal withdrawal reflex and colonic transport test results. The development of PI-IBS was associated with an increase in intestinal γδ T cells and cytokines including interleukin-1 (IL-1), IL-6, IL-17A and interferon-α (IFN-α). In addition, γδ T cells obtained by purification in vitro could express A2AR and promote IL-1, IL-6, IL-17A and IFN-α secretion, which is also regulated by A2AR agonists and antagonists. We also found that A2AR antagonists improved γδ T cell function through the PKA/CREB/NF-κB signaling pathway.

Research conclusions

Our results suggested that A2AR contributes to the development of PI-IBS after T. spiralis infection via the PKA/CREB/NF-κB signaling pathway by γδ T cells.

Research perspectives

Hypo-inflammation caused by immune dysfunction is considered to be one of the main pathogenic mechanisms of PI-IBS. In this study, we discovered that A2AR on the surface of γδ T cells can regulate the function of γδ T cell, thereby increasing inflammatory factor secretion and promoting PI-IBS progression. Luckily, the utilization of A2AR antagonists can improve PI-IBS symptoms by promoting γδ T cells’ function. Through our study, we identified A2AR, a key protein that promotes PI-IBS disease progression, and demonstrated the feasibility of antagonizing A2AR to intervene in PI-IBS, thus providing a novel therapeutic target and an effective intervention strategy for PI-IBS treatment.