Project Details
Description
PROJECT SUMMARY/ABSTRACT
The long-term objective of this project is to investigate the fundamental immunological mechanisms
involved in the development of asthma and allergic diseases. It is becoming increasingly clear that cytokines
produced by epithelial cells, including thymic stromal lymphopoietin, IL-25, and IL-33, play an important role in
shaping type 2 immunity and in the pathophysiology of allergic diseases. However, major gaps remain in our
knowledge concerning the molecular and cellular control of production and secretion of these cytokines. In this
application, we will investigate the mechanisms involved in IL-33 secretion.
IL-33 is primarily stored in the nucleus of non-hematologic cells; nuclear localization is a unique feature of
this cytokine. We previously found that exposure of human airway epithelial cells to a fungal allergen,
Alternaria alternata, evokes rapid extracellular release of ATP, which triggers sustained increases in
intracellular calcium concentration and IL-33 secretion into the extracellular milieu. We also found that airway
epithelial cells release acetylcholine (ACh) extracellularly following Alternaria or house dust mite allergen
exposure. Importantly, blocking M3 muscarinc receptors (M3R) on epithelial cells suppressed ATP release and
IL-33 secretion, suggesting an autocrine role for ACh. Therefore, we hypothesize that allergen-induced ACh
secretion by the airway epithelium plays a pivotal role in triggering a sequence of intracellular events that lead
to extracellular release of IL-33.
The experiments described in this proposal will investigate key steps of this process in detail. In Aim 1,
we will deterimne how airborne allergen exposure triggers ACh secretion and early cellular responses in airway
epithelial cells in vitro. In Aim 2, we will investigate how epithelium-derived ACh facilitates IL-33 secretion by
focusing on the autocrine ACh/M3R signaling pathway and protein kinase C-dependent phosphorylation of key
regulatory proteins. In Aim 3, we will investigate the role of epithelial ACh/M3R signaling in allergen-induced IL-
33 secretion and initiation of type 2 immunity in the lung by using mouse models of allergic inflammation.
We will employ a combination of complementary expertise in molecular and cell biology, pharmacology
and immunology in the laboratories of Dr. O’Grady and Dr. Kita. Novel and robust in vitro and in vivo models
have been developed for this project. These studies will provide a better understanding of how the epithelium
responds to environmental allergens and will define key cellular and molecular mechanisms responsible for
secretion of IL-33. Ultimately, these studies will characterize critical mechanism(s) involved in allergen-induced
immune responses, allowing for identification of novel therapeutic target(s) to treat and ideally prevent
immune-mediated airway diseases, such as asthma, chronic rhinosinusitis, and other allergic disorders.
Status | Active |
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Effective start/end date | 12/16/16 → 1/31/25 |
Funding
- National Institute of Allergy and Infectious Diseases: $630,120.00
- National Institute of Allergy and Infectious Diseases: $609,009.00
- National Institute of Allergy and Infectious Diseases: $522,735.00
- National Institute of Allergy and Infectious Diseases: $510,759.00
- National Institute of Allergy and Infectious Diseases: $509,737.00
- National Institute of Allergy and Infectious Diseases: $521,369.00
- National Institute of Allergy and Infectious Diseases: $516,518.00
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