Basic Study
Copyright ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jul 7, 2022; 28(25): 2955-2967
Published online Jul 7, 2022. doi: 10.3748/wjg.v28.i25.2955
Upregulated adenosine 2A receptor accelerates post-infectious irritable bowel syndrome by promoting CD4+ T cells’ T helper 17 polarization
Li-Wei Dong, Zhi-Chao Ma, Jiao Fu, Bai-Li Huang, Fu-Jin Liu, Deming Sun, Cheng Lan
Li-Wei Dong, 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
Deming 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 and Lan C designed the study and interpreted the findings; Dong LW and Ma ZC performed the experiments, analyzed the data, and drafted the manuscript; Fu J, Huang BL and Liu FJ helped collect and analyze the data; Sun D and Lan C critically revised the manuscript for important intellectual content and reviewed the article; all authors have read and approved the final manuscript.
Supported by National Natural Science Foundation of China, No. 81160057, No. 81860102, and No. 82060102.
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: February 14, 2022
Peer-review started: February 14, 2022
First decision: April 12, 2022
Revised: April 26, 2022
Accepted: June 13, 2022
Article in press: June 13, 2022
Published online: July 7, 2022
Processing time: 140 Days and 3.3 Hours
Abstract
BACKGROUND

Post-infectious irritable bowel syndrome (PI-IBS) is generally regarded as a functional disease. Several recent studies have reported the involvement of low-grade inflammation and immunological dysfunction in PI-IBS. T helper 17 (Th17) polarization occurs in IBS. Adenosine and its receptors participate in intestinal inflammation and immune regulation.

AIM

To investigate the role of Th17 polarization of CD4+ T cells regulated by adenosine 2A receptor (A2AR) in PI-IBS.

METHODS

A PI-IBS model was established by infecting mice with Trichinella spiralis. The intestinal A2AR and CD4+ T lymphocytes were detected by immunohistochemistry, and the inflammatory cytokines were detected by enzyme-linked immunoassay. CD4+ T lymphocytes present in the animal’s spleen were separated and cultured with or without A2AR agonist and antagonist. Western blotting and real-time quantitative polymerase chain reaction were performed to determine the effect of A2AR on the cells and intestinal tissue. Cytokine production was determined. The protein and mRNA levels of A2AR associated signaling pathway molecules were also evaluated. Furthermore, A2AR agonist and antagonist were injected into the mouse model and the clinical features were observed.

RESULTS

The PI-IBS mouse model showed increased expression of ATP and A2AR (P < 0.05), and inhibition of A2AR improved the clinical features in PI-IBS, including the abdominal withdrawal reflex and colon transportation test (P < 0.05). The number of intestinal CD4+ T cells and interleukin-17 (IL-17) protein levels increased during PI-IBS, which was reversed by administration of the A2AR antagonist (P < 0.05). CD4+ T cells expressed A2AR and produced IL-17 in vitro, which was regulated by the A2AR agonist and antagonist. The A2AR antagonist increased the production of IL-17 by CD4+ T cells via the Janus kinase-signal transducer and activator of transcription-receptor-related orphan receptor γ signaling pathway.

CONCLUSION

The results of the present study suggested that the upregulation of A2AR increases PI-IBS by promoting the Th17 polarization of CD4+ T cells.

Keywords: Adenosine 2A receptor; CD4+ T cells; T helper 17 polarization; Post-infectious irritable bowel syndrome; Regulation

Core Tip: T helper 17 (Th17) polarization occurs during the development of irritable bowel syndrome (IBS). Adenosine and its receptors participate in the development of intestinal inflammation and immune regulation. Here, we found that the intestinal levels of ATP, adenosine 2A receptor (A2AR), and interleukin-17 (IL-17) and the number of CD4+ T cells increased in post-infectious IBS (PI-IBS) mice. In addition, A2AR promoted CD4+ T cells’ IL-17 production. Upregulated A2AR accelerated PI-IBS by promoting CD4+ T cells’ Th17 polarization, which was reversed by the A2AR antagonist. Thus, our results prove that the regulation of CD4+ T cells’ Th17 polarization by A2AR plays a pathogenetic role in the development of PI-IBS.