IL-33/ST2 signaling sustains hepato-intestinal homeostasis during Chagas disease by orchestrating immune regulation

Chagas disease, caused by Trypanosoma cruzi, presents a complex challenge due to persistent parasite presence and host-driven immunopathology. Current treatments often focus on parasite eradication but struggle with the chronic inflammatory and fibrotic sequelae. The IL-33/ST2 axis is recognized for its role in regulating type 2 immunity and tissue repair, yet its specific contribution to preserving tissue homeostasis during chronic infections like Chagas disease has remained poorly understood. This study addresses this gap by investigating how this pathway influences systemic and organ-specific responses.

Researchers investigated the role of IL-33/ST2 signaling in coordinating hepato-intestinal responses and systemic immunity during chronic T. cruzi infection. They utilized ST2-deficient (ST2-/-) BALB/c mice and wild-type controls, following them for up to 100 days postinfection. The study assessed coordinated systemic disturbances, including platelet counts and albumin levels. At the tissue level, endpoints included hepatic inflammation and fibrotic remodeling, colonic nitric oxide production, parasite clearance, and structural alterations. Immune cell profiles, including patrolling monocytes, monocyte-derived dendritic cells, and macrophage regulatory activity, were also characterized to understand the underlying immune regulatory circuits.

ST2 deficiency led to significant coordinated systemic disturbances, including platelet expansion and hyperalbuminemia. At the tissue level, loss of ST2 markedly exacerbated hepatic inflammation and fibrotic remodeling. In the colon, ST2-/- mice displayed increased nitric oxide production and enhanced parasite clearance, but critically, developed marked structural alterations. The absence of ST2 was associated with a reduction in patrolling monocytes, suggesting impaired homeostatic endothelial monitoring. This altered profile coincided with inflammatory monocyte-derived dendritic cell differentiation and lowered macrophage regulatory activity. These changes were linked to amplified IL-12-driven Th1 and cytotoxic T-cell responses, while simultaneously impairing IL-10-associated regulatory niches, ultimately resulting in severe multiorgan inflammation. These findings highlight the critical role of IL-33/ST2 in maintaining immunoregulatory balance.

The loss of ST2 signaling resulted in a profound shift towards inflammatory responses, marked by amplified IL-12-driven Th1 and cytotoxic T-cell activity, while simultaneously impairing IL-10-associated regulatory niches, culminating in severe multiorgan inflammation.