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Cul5 dampens cytokine sensing in Type II lymphocytes to prevent allergic airways remodeling

Award Number: R01AI187222
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/04/2026
PERIOD OF PERFORMANCE END DATE: 01/31/2031

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Cul5 dampens cytokine sensing in Type II lymphocytes to prevent allergic airways remodeling - PROJECT SUMMARY 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $670,017 )
2026	2026	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	1	2/4/2026	NEW	$670,017
														Subtotal = $670,017

Grand Total All Awards = $670,017

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Cul5 dampens cytokine sensing in Type II lymphocytes to prevent allergic airways remodeling

Award Number: R01AI187222

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 02/04/2026

PERIOD OF PERFORMANCE END DATE: 01/31/2031

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