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.