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.
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.
|Cahill, Katherine N; Raby, Benjamin A; Zhou, Xiaobo et al. (2016) Impaired E Prostanoid2 Expression and Resistance to Prostaglandin E2 in Nasal Polyp Fibroblasts from Subjects with Aspirin-Exacerbated Respiratory Disease. Am J Respir Cell Mol Biol 54:34-40|
|Buchheit, Kathleen M; Cahill, Katherine N; Katz, Howard R et al. (2016) Thymic stromal lymphopoietin controls prostaglandin D2 generation in patients with aspirin-exacerbated respiratory disease. J Allergy Clin Immunol 137:1566-1576.e5|
|Liu, Tao; Kanaoka, Yoshihide; Barrett, Nora A et al. (2015) Aspirin-Exacerbated Respiratory Disease Involves a Cysteinyl Leukotriene-Driven IL-33-Mediated Mast Cell Activation Pathway. J Immunol 195:3537-45|
|Liu, Tao; Garofalo, Denise; Feng, Chunli et al. (2015) Platelet-driven leukotriene C4-mediated airway inflammation in mice is aspirin-sensitive and depends on T prostanoid receptors. J Immunol 194:5061-8|
|Cahill, Katherine N; Bensko, Jillian C; Boyce, Joshua A et al. (2015) Prostaglandin Dâ‚‚: a dominant mediator of aspirin-exacerbated respiratory disease. J Allergy Clin Immunol 135:245-52|
|Boyce, Joshua A; Barrett, Nora A (2015) Cysteinyl leukotrienes: an innate system for epithelial control of airway smooth muscle proliferation? Am J Respir Crit Care Med 191:496-7|
|Kanaoka, Yoshihide; Boyce, Joshua A (2014) Cysteinyl leukotrienes and their receptors; emerging concepts. Allergy Asthma Immunol Res 6:288-95|
|Laidlaw, Tanya M; Cutler, Anya J; Kidder, Molly S et al. (2014) Prostaglandin E2 resistance in granulocytes from patients with aspirin-exacerbated respiratory disease. J Allergy Clin Immunol 133:1692-701.e3|
|Kondeti, Vinay; Duah, Ernest; Al-Azzam, Nosayba et al. (2013) Differential regulation of cysteinyl leukotriene receptor signaling by protein kinase C in human mast cells. PLoS One 8:e71536|
|Ohta, Shin; Imamura, Mitsuru; Xing, Wei et al. (2013) Group V secretory phospholipase A2 is involved in macrophage activation and is sufficient for macrophage effector functions in allergic pulmonary inflammation. J Immunol 190:5927-38|
Showing the most recent 10 out of 18 publications