Epstein-Barr virus infection exacerbates ulcerative colitis by driving macrophage pyroptosis via the upregulation of glycolysis

Abstract

Background: Epstein-Barr virus (EBV) infection is associated with clinical symptoms, treatment response, need for surgical intervention, and an enhanced likelihood of lymphoma among patients with ulcerative colitis (UC). However, existing studies have primarily concentrated on the epidemiological and clinical associations between EBV and UC, leaving the mechanisms by which EBV exacerbates colitis poorly understood.

Methods: Clinical specimens of UC patients with EBV infection and a mouse model of dextran sulfate sodium-induced colitis with concurrent murine γ-herpesvirus 68 (MHV-68) infection were utilized to investigate the relationship between EBV infection and macrophage pyroptosis. In vivo, adoptive transfer of MHV-68-induced macrophages and macrophage depletion were performed to elucidate the underlying mechanisms. In vitro, myeloid leukemia mononuclear cells of human (THP-1) and macrophages derived from mouse bone marrow (BMDMs) were stimulated with EBV and MHV-68, respectively, to assess macrophage pyroptosis and glycolysis.

Results: EBV-induced activation of macrophage pyroptosis was positively correlated with clinical disease activity in UC patients. Furthermore, MHV-68 infection activated pyroptosis by upregulating gasdermin D, NLRP3, interleukin-1β, and interleukin-18 in colonic tissues and peritoneal macrophages of mice with colitis. In vitro, EBV and MHV-68 also mediated activation of pyroptosis in human THP-1 cells and mouse BMDMs, respectively. Additionally, the adoptive transfer of MHV-68-induced BMDMs aggravated murine colitis, whereas macrophage depletion attenuated MHV-68-induced intestinal injury. Mechanistically, MHV-68 promoted macrophage pyroptosis by upregulating glycolysis, while the glycolysis inhibitor, 2-deoxy-D-glucose, blocked this process in vitro.

Conclusion: EBV infection exacerbates UC by driving macrophage pyroptosis through upregulation of glycolysis, indicating a potential therapeutic approach to mitigate EBV-induced intestinal inflammation.

Keywords

Epstein-Barr virus / ulcerative colitis / macrophages / pyroptosis; glycolysis

Acknowledgements

This work was supported by the Science and Technology Foundation of Sichuan Province of China (Grants No. 2023YFS0279 and 2024YFFK0347).

Author contributions

Chunxiang Ma (Formal analysis, Investigation, Methodology, Validation, Visualization, Writing—original draft), Kexin Chen (Formal analysis, Investigation, Methodology, Validation, Visualization, Writing—original draft), Lili Li (Formal analysis, Investigation, Methodology, Validation, Visualization, Writing—original draft), Mingshan Jiang (Investigation, Writing—review & editing), Zhen Zeng (Investigation, Writing—review & editing), Fang Yin (Investigation, Writing—review & editing), Jing Yuan (Investigation, Writing—review & editing), Yongbin Jia (Investigation, Writing—review & editing), and Hu Zhang (Conceptualization, Funding acquisition, Project administration, Resources, Supervision, Writing—original draft, Writing—review & editing).

Supplementary data

Supplementary data are available at PCMEDI online.

Conflict of interest

None declared. In addition, as an Editorial Board Member of Precision Clinical Medicine, the corresponding author Hu Zhang was blinded from reviewing and making decisions on this manuscript.

Ethics approval

This study followed the tenets of the Declaration of Helsinki and was approved by the ethics committee of West China Hospital (2023-22). The Ethics Committee waived the need for informed consent due to the retrospective nature of this study, according to the Ethical Guideline for Clinical Research issued by National Health Commission of the People's Republic of China. All animal experiments were approved by the Animal Ethics Committee of West China Hospital, Sichuan, China (Approval Number: 20220207002).

Data availability

All relevant data are contained within the article and the supplementary material. Additional data supporting the findings of this article are available from the corresponding author upon reasonable request.

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