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Neuroimmune interactions regulate development of allergic inflammation

Award Number: R37AI139536
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: 11/28/2023
PERIOD OF PERFORMANCE END DATE: 10/31/2028

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Neuroimmune interactions regulate development of allergic inflammation - PROJECT SUMMARY Atopy, Asthma and food allergies are highly prevalent inflammatory disorders that are increasing at an epidemic rate. Progression of allergies from one system to other, ultimately involving multiple organs, called “atopic march” is not uncommon in infancy. Aberrant type 2 immune responses to allergens have long been appreciated as the major driver of allergic reactions, with symptoms of very severe bronchospasms in asthma to vomiting and diarrhea observed in food allergies. Type II cytokines (IL-4 and IL-13) are both the drivers and effector molecules that drive allergic reactions. It is believed that IL-4 and IL-13 cytokines work on innate and adaptive immune system to induce and perpetuate type II inflammatory allergic reactions. We undertook a scRNAseq analysis to identify the cell types where IL-13R is expressed and we identified a cluster of enteric sensory neurons and multiple clusters of DRG and nodose ganglion neurons that express IL-13-specific receptors. This raises the issue of what is the role of IL-13R on the sensory neurons in the lung and gut in regulating allergic inflammation. Our preliminary data show that enteric neuron-specific deletion of IL-13R (Il13ra1) failed to control the worm burden and fecundity of the intestinal helminth parasite Heligmosomoides Polygyrus (Hp). Furthermore, Hp-infected Il13ra1 conditional knock-out (cKO) mice displayed severe impairments in the upregulation of Nmu and Calcb neuropeptide expression, suggesting neuronal IL-4/IL-13-receptor signaling contributes to the amplification of immunomodulatory neuropeptide expression during intestinal helminth infection. Initial scRNAseq of the immune and non-immune cells of the intestines of the Hp- infected IL-13R conditional knock-out mice suggest epithelial cell reprogramming and reduction is the number of ILC2. Based on these preliminary data, we hypothesize that cytokine-neuropeptide feedback loops between immune cells and neurons regulate type 2 inflammation and the development of type II allergic inflammation. We propose two specific aims to address this hypothesis: 1) Determine the role of type -2 cytokine receptor, specifically IL-13R signaling in neurons for the development of type 2 inflammation in the lung and gut; 2) How do the cytokine receptors on enteric neurons affect barrier integrity and host defense? Together these two aims will begin to address the functional role of type II cytokine receptors (specifically IL-13R) in regulating neuronal activation, neuropeptide production, and development of type II inflammation. The project will also focus on characterizing novel molecular interactions between cytokines, neurons and the immune system to regulate the differentiation and function of the innate and adaptive immune system, with an ultimate aim to find translatable therapeutic targets for chronic allergic diseases.


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 = $602,703 )
2026	2026	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	8	12/2/2025	NON-COMPETING CONTINUATION	$602,703
														Subtotal = $602,703

Issue Date FY: 2025 ( Subtotal = $584,623 )
2025	2025	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	7	10/30/2024	NON-COMPETING CONTINUATION	$584,623
														Subtotal = $584,623

Issue Date FY: 2024 ( Subtotal = $602,800 )
2024	2024	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	001	6	8/9/2024	COMPETING CONTINUATION	$0
2024	2024	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	6	11/28/2023	COMPETING CONTINUATION	$542,522
2024	2024	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	002	6	9/3/2024	COMPETING CONTINUATION	$60,278
														Subtotal = $602,800

Grand Total All Awards = $1,790,126

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Neuroimmune interactions regulate development of allergic inflammation

Award Number: R37AI139536

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: 11/28/2023

PERIOD OF PERFORMANCE END DATE: 10/31/2028

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