Dysbiosis drives allergic inflammation independent of IL-33/ST2 signaling 2260035

Abstract Introduction The IL-1 family cytokine IL-33 plays a role in many inflammatory diseases including atherosclerosis, fibrosis, COPD, and asthma. As a pleotropic alarmin, IL-33 is an innate mediator of Th2 immunity and a coveted clinical target. However, while a-IL-33 therapeutics have advanced to clinical trials none have been efficacious enough for regulatory approval. Hence, the incomplete understanding of contextual IL-33 function is a detriment to its therapeutic use. In the literature, mice lacking IL-33 (IL-33-/-) or ST2 (ST2-/-) exhibit a reduced response to allergen, demonstrating the necessity of IL-33/ST2 signaling. Paradoxically, ST2-/- mice in our studies respond to allergen comparably to controls, indicating that alternative pathways to inflammation can be sufficient. These data led us to the intriguing hypothesis that the environment can drive IL-33/ST2-independent inflammation, perhaps via the microbiome. Methods A house dust mite model of acute allergic inflammation was used to compare the allergic responses of ST2-/- mice from two facilities, A and B, quantified by flow cytometry and histology. Antibiotic depletion was performed to test the effect of the microbiome. Results Our data show that ST2-/- mice from Facility A exhibit an increased inflammatory response compared to those from Facility B, supporting an environmental effect. Excitingly, while inflammatory responses of WT and ST2-/- mice in Facility B were unaffected by microbiome depletion, the regimen resulted in a marked decrease in Th2 responses from Facility A ST2-/- mice. Conclusion Together, these data demonstrate that IL-33/ST2 signaling is only necessary to generate allergic inflammation in some environmental contexts, and that IL-33/ST2-independent allergic pathways are upregulated in a microbiome-dependent manner. By discerning the role of the microbiome in driving alternative pathways to allergic activation, the relationship between the environment and innate signaling can be better understood in broader disease contexts. Funding Source Immunology Training Grant- 5T32AI007496-28 Topic Categories Mucosal and Regional Immunology (MUC)