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
Abstract
BACKGROUND

Immunological dysfunction-induced low-grade inflammation is regarded as one of the predominant pathogenetic mechanisms in post-infectious irritable bowel syndrome (PI-IBS). γδ T cells play a crucial role in innate and adaptive immunity. Adenosine receptors expressed on the surface of γδ T cells participate in intestinal inflammation and immunity regulation.

AIM

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

METHODS

The PI-IBS mouse model has been established with Trichinella spiralis (T. spiralis) infection. The intestinal A2AR and A2AR in γδ T cells were detected by immunohistochemistry, and the inflammatory cytokines were measured by western blot. The role of A2AR on the isolated γδ T cells, including proliferation, apoptosis, and cytokine production, were evaluated in vitro. Their A2AR expression was measured by western blot and reverse transcription polymerase chain reaction (RT-PCR). The animals were administered with A2AR agonist, or A2AR antagonist. Besides, γδ T cells were also injected back into the animals, and the parameters described above were examined, as well as the clinical features. Furthermore, the A2AR-associated signaling pathway molecules were assessed by western blot and RT-PCR.

RESULTS

PI-IBS mice exhibited elevated ATP content and A2AR expression (P < 0.05), and suppression of A2AR enhanced PI-IBS clinical characteristics, indicated by the abdominal withdrawal reflex and colon transportation test. PI-IBS was associated with an increase in intestinal T cells, and cytokine levels of interleukin-1 (IL-1), IL-6, IL-17A, and interferon-α (IFN-α). Also, γδ T cells expressed A2AR in vitro and generated IL-1, IL-6, IL-17A, and IFN-α, which can be controlled by A2AR agonist and antagonist. Mechanistic studies demonstrated that the A2AR antagonist improved the function of γδ T cells through the PKA/CREB/NF-κB signaling pathway.

CONCLUSION

Our results revealed that A2AR contributes to the facilitation of PI-IBS by regulating the function of γδ T cells via the PKA/CREB/NF-κB signaling pathway.

Keywords: Irritable bowel syndrome, Adenosine 2A receptor, γδ T cells, Post-infectious irritable bowel syndrome, Signaling pathway, Regulation

Core Tip: Immunological dysfunction-induced low-grade inflammation is regarded as one of the most important pathogenetic mechanisms in post-infectious irritable bowel syndrome. γδ T cells play a crucial role in innate and adaptive immunity. The adenosine molecule and receptors regulate intestinal inflammation and immunity. Through the PKA/CREB/NF-κB signaling pathway, we showed that adenosine 2A receptor contributes to the facilitation of post-infectious irritable bowel syndrome by T cells.