IL-22-STAT3-CD155 axis in alveolar echinococcosis: a pivotal role in immune exhaustion and therapeutic potential

Liang Li^1,2Xue Zhang^1,2Ning Yang^1,2Hui Liu^1,2Junlong Xue^1,2Jin Chu^1,2GUODONG LYU^1,2Tuerganaili Aji^2,3*Xiaojuan Bi^1,2*Renyong Lin^1,2*

• ¹Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases, Xinjiang Medical University, Urumqi, China
• ²The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
• ³Department of Hepatobiliary and Hydatid Diseases, Digestive and Vascular Surgery Center, Urumqi, China

Background: Alveolar echinococcosis (AE), a lethal zoonosis caused by Echinococcus multilocularis (E.m) infection, is characterized by immune exhaustion that facilitates parasite evasion of host immunity and sustains chronic infection. The role and mechanisms of Interleukin-22 (IL-22), a key immunomodulatory cytokine, in E.m-induced immune responses remain unclear and warrant investigation. Methods: Liver tissue samples from AE patients and E.m-infected mouse models were utilized to investigate IL-22 expression dynamics during AE progression and its correlation with disease progression. Recombinant IL-22 (rIL-22) stimulation and IL-22-binding protein (rIL-22BP) blockade were integrated to comprehensively assess the role of IL-22 through Western blotting, immunohistochemistry (IHC), and enzyme-linked immunosorbent assay (ELISA). Pathological alterations in infected mice were quantified via hematoxylin and eosin (H&E) and Sirius Red staining to evaluate the potential of IL-22 as a therapeutic target. Flow cytometry and in vitro co-culture systems were further employed to identify the cellular sources of IL-22 and elucidate its regulatory effects on CD155 expression in hepatocytes. Results: IL-22 expression was significantly upregulated in liver tissues from both AE patients and E.m-infected mice, positively correlating with disease progression. Compared with the infection group (Em), rIL-22 stimulation exacerbated parasitic burden, increasing lesion number and fibrotic area. Conversely, rIL-22BP blockade effectively attenuated pathology, significantly reducing lesion burden and fibrotic area. Mechanistically, in vitro co-culture experiments demonstrated that macrophage-derived IL-22 activated STAT3 signaling in hepatocytes, upregulating CD155 expression, which is a key mechanism underlying E.m-induced immune exhaustion. rIL-22BP treatment disrupted IL-22-CD155 intercellular crosstalk, promoting CD8⁺ T-cell recruitment to lesions and reversing their exhausted state. Conclusion: Our study demonstrates that the IL-22–STAT3–CD155 axis, mediated by macrophage-hepatocyte crosstalk, drives the establishment of an immune-exhaustive microenvironment during E.m infection. Mechanistically, macrophage-derived IL-22 induces CD155 upregulation in hepatocytes via IL-22RA1/STAT3 signaling. Critically, rIL-22BP blockade disrupts this axis, reversing the immunosuppressive cascade, restoring CD8⁺ T-cell effector functions, and remodeling the immune microenvironment. This intervention ultimately enhances host-mediated clearance of E.m.