Dysregulated IL-33/ST2 axis in hemochromatotic hosts aggravates susceptibility to the Yersinia enterocolitica infection 2259344

Abstract

Abstract Introduction Iron is essential for host metabolism but becomes toxic in excess, disrupting immune balance. Hemochromatosis (iron overload) heightens susceptibility to severe bacterial infections. Although IL-33 maintains mucosal homeostasis via the IL-33/ST2 axis on Tregs, it’s regulation under hemochromatosis remains unclear. Here, we show that excess iron rewires IL-33 responses, converting it from a regulatory cytokine to a pathogenic inflammation driver during Yersinia enterocolitica (YE) infection. Methods Mice were on a high iron diet for 4 weeks to generate iron overload followed by infection with YE. Control mice were fed control diet with normal iron. Results IL-33 was identified as a key mediator of iron-induced YE disease exacerbation, as IL-33 deficiency conferred marked protection, reducing neutrophilia, inflammatory cytokines, and multi-organ injury. Mechanistically, iron overload first upregulated IL-33 expression, and subsequent YE infection triggered excessive IL-33 release, driving lethal inflammation. Iron excess in also reprogrammed IL-33 receptor (ST2) expression by reducing ST2 expression on T regulatory cells (Treg) and their IL-13 secretion while enhancing ST2 expression on neutrophil and macrophages; thereby suppressing regulatory immunity and amplifying innate inflammation. Myeloid-specific ST2 deletion reduced cytokine storm and improved survival, whereas adoptive transfer of functional ST2+ Tregs or recombinant IL-13 restored immune regulation and protection. Conclusion The study reveal a previously unrecognized a nutritional—cytokine checkpoint in wherein excess iron dysregulates the IL-33/ST2 signaling, silencing Treg cell function and amplifying pathogenic IL-33 responses in myeloid cells. This dual reprogramming converts IL-33 from a tissue-protective alarmin into a proinflammatory amplifier that predisposes iron-overloaded hosts to lethal YE infection. Therapeutically, targeting the IL-33/ST2 axis or restoring Treg function may mitigate iron-driven inflammatory pathology. Funding Source NIH R01AI162670 Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)