IL ‐33/ ST 2 Signaling Sustains Hepato‐Intestinal Homeostasis by Orchestrating Vascular Surveillance and Immune Regulatory Circuits During Experimental Trypanosoma cruzi Infection

ABSTRACT Chagas disease, caused by Trypanosoma cruzi , is characterized by a complex interplay between parasite persistence and host‐driven immunopathology. Although the IL‐33/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‐deficient (ST2 −/− ) and wild‐type BALB/c mice followed for up to 100 days postinfection, we investigated the role of IL‐33/ST2 signaling in coordinating hepato–intestinal 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 −/− mice displayed increased nitric oxide production and enhanced parasite clearance, but developed marked structural alterations. Our findings suggest that IL‐33/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‐derived dendritic cell differentiation and lowered macrophage regulatory activity. This altered profile was associated with amplified IL‐12–driven Th1 and cytotoxic T‐cell responses while impairing IL‐10–associated regulatory niches, resulting in multiorgan inflammation. These findings suggest that IL‐33/ST2 signaling may contribute to immunoregulatory balance during T. cruzi infection and identify this axis as a candidate pathway for future mechanistic and therapeutic investigation.