{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T00:28:39Z","timestamp":1792456119130,"version":"4.5.0"},"reference-count":37,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T00:00:00Z","timestamp":1767571200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Alveolar echinococcosis (AE), a lethal zoonosis caused by\n                      <jats:italic>Echinococcus multilocularis<\/jats:italic>\n                      (\n                      <jats:italic>E.m<\/jats:italic>\n                      ) 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\n                      <jats:italic>E.m<\/jats:italic>\n                      -induced immune responses remain unclear and warrant investigation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Liver tissue samples from AE patients and\n                      <jats:italic>E.m<\/jats:italic>\n                      -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&amp;amp;E) and Sirius Red staining to evaluate the potential of IL-22 as a therapeutic target. Flow cytometry and\n                      <jats:italic>in vitro<\/jats:italic>\n                      co-culture systems were further employed to identify the cellular sources of IL-22 and elucidate its regulatory effects on CD155 expression in hepatocytes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      IL-22 expression was significantly upregulated in liver tissues from both AE patients and\n                      <jats:italic>E.m<\/jats:italic>\n                      -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,\n                      <jats:italic>in vitro<\/jats:italic>\n                      co-culture experiments demonstrated that macrophage-derived IL-22 activated STAT3 signaling in hepatocytes, upregulating CD155 expression, which is a key mechanism underlying\n                      <jats:italic>E.m<\/jats:italic>\n                      -induced immune exhaustion. rIL-22BP treatment disrupted IL-22-CD155 intercellular crosstalk, promoting CD8\n                      <jats:sup>+<\/jats:sup>\n                      T-cell recruitment to lesions and reversing their exhausted state.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Our study demonstrates that the IL-22\u2013STAT3\u2013CD155 axis, mediated by macrophage-hepatocyte crosstalk, drives the establishment of an immune-exhaustive microenvironment during\n                      <jats:italic>E.m<\/jats:italic>\n                      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\n                      <jats:sup>+<\/jats:sup>\n                      T-cell effector functions, and remodeling the immune microenvironment. This intervention ultimately enhances host-mediated clearance of\n                      <jats:italic>E.m<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1674904","type":"journal-article","created":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T07:43:34Z","timestamp":1767599014000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["IL-22-STAT3-CD155 axis in alveolar echinococcosis: a pivotal role in immune exhaustion and therapeutic 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