CUL5 dampens cytokine sensing in type II lymphocytes to prevent allergic airways remodeling

The National Institute of Allergy and Infectious Diseases awarded The Children's Hospital of Philadelphia $670,017 on February 4, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to define a regulatory pathway in type 2 innate lymphoid cells that prevents chronic allergic lung inflammation and airways hyperresponsiveness.

The award funds research into the E3 ubiquitin ligase CUL5 and its role in restricting cytokine receptor signaling in ILC2s. Preliminary data demonstrates that CUL5 expression in ILC2s protects lungs from allergic inflammation, while mice lacking CUL5 in ILC2s show increased numbers and function of lung IL-33R+ ILC2s, increased sub-epithelial fibrosis, and increased airways hyperresponsiveness following fungal allergen exposure. The research addresses asthma as a chronic inflammatory disease affecting 26 million Americans with approximately 3,600 deaths annually in the United States alone.

The recipient, The Children's Hospital of Philadelphia Research Institute operating as Children's Hospital of Philadelphia Foundation, performs the work in Philadelphia, Pennsylvania. The period of performance extends from February 4, 2026, through January 31, 2031. The award is classified as a Project Grant, a standard assistance type under the NIH Allergy and Infectious Diseases Research program supporting investigator-initiated biomedical research in infectious, immunologic, and allergic diseases.

Abstract

The goal of this proposal is to define a novel regulatory pathway in type 2 lymphocytes that prevents chronic allergic lung inflammation and airways hyperresponsiveness. Asthma is a chronic inflammatory disease of the airways that affects 26 million americans and results in approximately 3600 deaths per year in the US alone. Over the past 40 years, the incidence of asthma has increased across the US2. The underlying pathology of asthma is complex, and in many instances poorly understood. New therapies are being introduced that take advantage of our understanding of the importance of type II cytokines (IL-4, IL-5, IL-13). We have identified a regulatory pathway in innate type 2 lymphocytes (ILC2S) that restricts cytokine receptor signaling and thus limits ILC2 numbers and cytokine production following helminth or fungal allergen exposure. This regulatory circuit is under the control of the E3 ubiquitin ligase CUL5 and its socs-box containing substrate receptors. Our preliminary data demonstrate that CUL5 expression in ILC2S protects lungs from allergic inflammation. Mice lacking CUL5 in ILC2S showed increased numbers and function of lung IL-33R+ ILC2S, increased sub-epithelial fibrosis, and increased airways hyperresponsiveness following fungal allergen exposure. Interestingly, we also identified a significant increase in the numbers of atypical IL-18R+ ILC2S in the lungs. These are ILC2S more commonly seen in the skin. Intranasal administration of RIL-33 or RIL-18 resulted in increased numbers of CUL5- deficient lung ILC2 cells. This was particularly surprising given that CUL5 is largely thought to limit JAK/stat signaling and IL-18 and IL-33 receptors are IL-1 family receptors that signal thru MYD88/nfkb. Based on our preliminary data, we posit that CUL5 works with one or more socs-box containing substrate receptors to limit signaling downstream of IL-18R and IL-33R, expansions of lung ILC2S, and decrease susceptibility to allergic inflammation in the lung. The studies proposed here will help US identify ways to strategically target CUL5 for therapeutic benefit. Furthermore, data from these studies will provide key information regarding how CUL5 limits type 2 responses, and how IT regulates cytokine signaling in IL-18R+ and IL-33R+ ILC2S in the lung.