IL-33/ST2-independent activation of lung type 2 responses - allergic asthma is a chronic inflammatory lung disease that causes an average of 1,000 deaths per day worldwide

The National Institute of Allergy and Infectious Diseases awarded the University of Virginia $236,660 on July 1, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to investigate IL-33-dependent and IL-33-independent pathways in allergic asthma.

The project examines how IL-33 signaling drives type-2 inflammatory responses in allergic asthma and why blockade of IL-33 has produced mixed clinical trial results despite its position as an upstream therapeutic target. The research uses mouse models to characterize the mechanisms by which the IL-33/ST2 axis functions in allergen-induced disease and to identify patient populations most likely to respond to anti-IL-33 therapeutics. The work addresses a specific phenomenon observed in the recipient's mouse facility, where IL-33 and ST2 deficiency did not produce the diminished allergic response to house dust mite allergen expected from prior literature, suggesting environmental or facility-specific factors influence the role of this signaling pathway in asthma pathogenesis.

Performance occurs in Charlottesville, Virginia through June 30, 2028. The award is a project grant providing assistance funding for biomedical research.

The innate response to allergen is mediated by alarmins such as IL-33, which are primarily released by epithelial cells. IL-33 secretion drives type-2 inflammation through its cognate receptor ST2. Given its highly pleiotropic nature and upstream positioning in the allergic response cascade, IL-33 is a coveted clinical target for amelioration of downstream pathology, yet there have been mixed results with IL-33 blockade in clinical trials. While multiple -IL-33 therapeutics have advanced to phases II & III of clinical trials, none have been efficacious enough to reach regulatory approval. The reason that modulation of IL-33 in patients does not effectively mitigate downstream asthmatic pathology remains elusive, and this variability may affect whether anti-IL-33 is efficacious in other diseases such as copd and respiratory infections. Thus, understanding the parameters of the IL-33- dependent and IL-33-independent pathways in mouse models of allergic asthma will provide mechanistic insight into how these therapeutics function in disease and help US to target the patients most likely to respond. IL-33 is key for the generation of allergic inflammation in mice, and mice lacking either IL-33 or ST2 have a greatly diminished response to allergens. However, when the sperling lab moved to UVA, we discovered that in our new mouse facility, the IL-33/ST2 signaling axis was dispensable. Our IL-33 and ST2 deficient mice robustly respond to house dust mite (HDM) allergen equal to littermate controls. To investigate whether this remarkable phenomenon was environmentally driven, we compared the allergic responses of our ST2-/- mice to those housed in another facility at UVA. While our ST2-/- mice maintained a strong allergic response in our model, ST2-/- mice from the different facility had the diminished response found previously. Thus, to our knowledge we are the first to demonstrate that IL-33/ST2 signaling is necessary for generating allergic inflammation in some environmental contexts, but not others. We then posit that the environmental driver of inflammation comes from the microbiome, which is known to influence asthma in humans. Antibiotic treatment resulted in a striking decrease in type 2 inflammation in our ST2-/- mice. Our overall hypothesis is that IL-33/ST2-independent allergic pathways are upregulated in a microbiome-dependent manner in our facility. To investigate this, we propose the following specific aims. 1) determine the effect of the GUT microbiome on IL-33/ST2-independent pathway activation and 2) elucidate compensatory IL-33/ST2-independent pathways of activation. Impact: the current paradigm is that the IL-33/ST2 pathway plays a key role in the initiation and expansion of type 2 immunity. Our findings demonstrate that the necessity of this pathway is linked to the GUT microbiome. Our proposed studies, when completed, will reveal the potential mechanisms involved in facilitating this crosstalk. Elucidating these mechanisms will provide important and testable clues about why anti-IL-33 therapeutics have been underwhelming in clinical trials and provide new approaches to improving their efficacy.