This application for continued support focuses on the role of the type 6 purinergic (P2Y6) receptor in the pathophysiology of house dust mite (HDM) allergen-induced pulmonary inflammation. In the previous funding cycle, we discovered that P2Y6 receptors, which are high affinity G protein-coupled receptors (GPCRs) for uridine diphosphate (UDP), cross-regulate the functions of the type 1 receptor for cysteinyl leukotrienes (cys- LTs), CysLT1R. We now demonstrate that P2Y6 receptors are major negative regulators of pulmonary inflammation induced by the intranasal administration of an extract (Df) from the HDM Dermatophagoides farinae. Repetitive intranasal administration of low doses of an extract (Df) from the HDM to C57BL/6 or BALB/c mice causes robust peribronchial and perivascular eosinophilia, goblet cell metaplasia, and a mixed T helper (Th)2, Th1, and Th17-type immune response in the lungs. The Th2 component of this response depends strongly on the expression of CysLT1R by dendritic cells (DCs), and the ability of DCs to generate cys-LTs. We have found the mice bearing a conditional knockout of the p2ry6 allele (p2ry6 (flox/flox);cre/+ mice, hereafter referred to as p2ry6-/- mice) develop markedly exacerbated peribronchial/perivascular inflammation compared with identically treated littermate p2ry6 (flox/flox) controls (hereafter referred to as +/+ mice) after receiving intranasal Df. Preliminary studies suggest that P2Y6 receptors control separate but distinct aspects of the phenotype through control of T cell and DC activation, respectively, with an especially important role in regulating CysLT1R-dependent Th2 priming by DCs. The primary hypothesis of this proposal that P2Y6 receptors inhibit the development of allergen-induced pulmonary inflammation through separate effects on Th2 priming by DCs at sensitization and on activation of T cells in the effector phase of the same response. A corollary hypothesis is that P2Y6 receptors exert control over the endogenous cys-LT-CysLT1R dependent pathway for Th2 priming by DCs via a PKC-dependent mechanism. The proposed studies will provide insight into the mechanisms by which common allergens elicit Th2 responses at sensitization, and may also provide a basis for developing effective pharmacologic agents that could attenuate Th2 sensitization by blocking CysLT1R without the off-target effects of blocking inhibitory signaling through P2Y6 receptors.

Public Health Relevance

Asthma is a common, serious disease that is often associated with allergy to house dust mites. This proposal seeks to determine how a protein called P2Y6, which is present on cells of the immune system, prevents the development of allergy to house dust mite. The studies will lead to insights that may permit the development of new medications to treat or prevent asthma and associated house dust mite allergy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AI052353-12
Application #
8595274
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Dong, Gang
Project Start
2002-08-01
Project End
2017-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
12
Fiscal Year
2014
Total Cost
$434,030
Indirect Cost
$170,920
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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