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Although the IL\u201033\/ST2 axis is known to regulate type 2 immunity and tissue repair, its contribution to tissue homeostasis during chronic infection remains poorly understood. Using ST2\u2010deficient (ST2\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    ) and wild\u2010type BALB\/c mice followed for up to 100\u2009days postinfection, we investigated the role of IL\u201033\/ST2 signaling in coordinating hepato\u2013intestinal response and systemic immunity. ST2 deficiency induced coordinated systemic disturbances, including platelet expansion and hyperalbuminemia. At the tissue level, loss of ST2 exacerbated hepatic inflammation and fibrotic remodeling. In the colon, ST2\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice displayed increased nitric oxide production and enhanced parasite clearance, but developed marked structural alterations. Our findings suggest that IL\u201033\/ST2 signaling is associated with regulatory programs. ST2 deficiency was associated with a reduction in patrolling monocytes, suggesting impaired homeostatic endothelial monitoring. This profile also coincided with inflammatory monocyte\u2010derived dendritic cell differentiation and lowered macrophage regulatory activity. This altered profile was associated with amplified IL\u201012\u2013driven Th1 and cytotoxic T\u2010cell responses while impairing IL\u201010\u2013associated regulatory niches, resulting in multiorgan inflammation. These findings suggest that IL\u201033\/ST2 signaling may contribute to immunoregulatory balance during\n                    <jats:styled-content style=\"fixed-case\">\n                      <jats:italic>T. cruzi<\/jats:italic>\n                    <\/jats:styled-content>\n                    infection and identify this axis as a candidate pathway for future mechanistic and therapeutic investigation.\n                  <\/jats:p>","DOI":"10.1096\/fj.202600565rr","type":"journal-article","created":{"date-parts":[[2026,7,5]],"date-time":"2026-07-05T17:09:43Z","timestamp":1783271383000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["<scp>IL<\/scp>\n                    \u201033\/\n                    <scp>ST<\/scp>\n                    2 Signaling Sustains Hepato\u2010Intestinal Homeostasis by Orchestrating Vascular Surveillance and Immune Regulatory Circuits During Experimental\n                    <i>Trypanosoma 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