Hepatic Alveolar Echinococcosis-Induced IL-23 Maintains Th17/Treg Homeostasis via the JAK2/STAT3 Signaling Pathway

Background To investigate the role of IL-23 in maintaining Th17/Treg homeostasis via the JAK2/STAT3 signaling pathway in patients with hepatic Alveolar echinococcosis (AE) and in experimental models, and to assess its potential value as an immunotherapeutic target and a biomarker of disease activity.Methods We conducted bioinformatic analysis and collected multiple research specimens, including liver tissue and peripheral blood samples from patients with hepatic AE, Echinococcus multilocularis (E.multilocularis) infected mice harvested at 4, 12 and 24 weeks post infection, and an in vitro cell co-culture system. The expression of IL-23 and Th17/Treg-related cytokines was measured by ELISA, IHC/IF, western blot (WB) and flow cytometry (FCM). We further explored the functional role of the IL-23/IL-17 axis using JAK2 inhibitor, STAT3 inhibitors and agonists, as well as IL-23 conditional knockout mice.Results Hepatic expression of IL-23A, p-JAK2 and p-STAT3 was significantly increased in AE patients and E.multilocularis-infected mice, and serum IL-23A levels were elevated and positively correlated with patients’ PET-CT SUVmax values. E.multilocularis infection induced high IL-23A expression in Kupffer cells and upregulation of IL-17A and RORγt. During infection, IL-23A expression increased early, peaked at the middle stage, and declined later. Th17-related factors followed a similar rise-and-fall pattern, whereas Treg-related factors increased continuously, shifting the Th17/Treg homeostasis from Th17 predominance early to Treg dominance at later stages. Inhibition of JAK2 or STAT3 reduced p-STAT3 and Th17 associated molecules and mildly upregulated Treg associated molecules, which could be partially reversed by a STAT3 agonist. In IL-23 conditional knockout mice, E.multilocularis infection resulted in increased metacestode burden and aggravated liver injury, accompanied by further suppression of Th17 responses, enhanced Treg responses, and reduced JAK2/STAT3 activation.Conclusion IL-23 sustains Th17/Treg homeostasis through the JAK2/STAT3 signaling pathway. It facilitates protective Th17 immune responses at the early infection stage and restrains excessive immunosuppression driven by dominant Treg cells during chronic infection. Conversely, IL-23 ablation disturbs this immune balance, which further inhibits Th17 responses and amplifies Treg-mediated immunosuppression, ultimately increasing metacestode burdens and aggravating hepatic injury.