Mast cells (MCs) are important in allergic diseases, tissue injury, and protection from infections. MC numbers and their effector functions are dynamically regulated by constituents of the tissue microenvironment. This application for continued support focuses on the role of cysteinyl leukotrienes (cys-LTs) and their receptors in the regulation of MC function. During the last funding period, we recognized that human MCs (hMCs) expressed both of the known receptors for cys-LTs (CysLT1 and CysLT2 receptors), and defined different functions for each. We identified specific modulatory functions for IL-4 in regulating cys-LT-dependent signaling events as well as CysLT2 receptor expression, and defined differential and complementary functions for the two cys-LT receptors by developing null strains of mice. Our preliminary studies now demonstrate that cys-LTs play an unanticipated, essential role in mediating reactive mastocytosis in a model of allergen-induced pulmonary inflammation. Both leukotriene C4 synthase-null mice (which cannot generate cys-LTs) and CysLT1 receptor-null mice completely lack MCs in the inflamed epithelial surfaces of the bronchi. Moreover, we have demonstrated that both cys-LTs and a nucleotide, UDP, behave as co-mitogenic growth factors for hMCs in vitro, acting by a pathway that requires CysLT1 receptors, Gi proteins, and the ERK MAP kinase cascade. Finally, we demonstrate that CysLT1 receptors on MCs constitutively form heterodimers with CysLT2 receptors and with UDP- selective P2Y6 receptors, respectively, and that each heterodimer differentially regulates the function of the therapeutically relevant CysLT1 receptor.
The Specific Aims are: 1. To determine the molecular basis and functional consequences of dimerization of P2Y6 and CysLT2 receptors with the CysLT1 receptor, and;2. To define the mechanisms through which P2Y6/CysLT1 receptors amplify stem cell factor (SCF)-dependent growth of hMCs, and mediate reactive mastocytosis in vivo using newly developed null mouse strains. Project Narrative: This proposal seeks to understand how a class of chemicals called cysteinyl leukotrienes control the function of mast cells, a type of immune cell. Since both mast cells and cysteinyl leukotrienes are important in asthma and are also believed to be important in heart disease and other conditions, these studies are anticipated to reveal potential new treatments for these common diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI052353-10
Application #
8204831
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Dong, Gang
Project Start
2002-08-01
Project End
2012-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
10
Fiscal Year
2012
Total Cost
$414,092
Indirect Cost
$169,067
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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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
Laidlaw, Tanya M; Boyce, Joshua A (2013) Pathogenesis of aspirin-exacerbated respiratory disease and reactions. Immunol Allergy Clin North Am 33:195-210
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
Cummings, Hannah E; Liu, Tao; Feng, Chunli et al. (2013) Cutting edge: Leukotriene C4 activates mouse platelets in plasma exclusively through the type 2 cysteinyl leukotriene receptor. J Immunol 191:5807-10
Fanning, Laura B; Boyce, Joshua A (2013) Lipid mediators and allergic diseases. Ann Allergy Asthma Immunol 111:155-62
Liu, Tao; Laidlaw, Tanya M; Feng, Chunli et al. (2012) Prostaglandin E2 deficiency uncovers a dominant role for thromboxane A2 in house dust mite-induced allergic pulmonary inflammation. Proc Natl Acad Sci U S A 109:12692-7
Laidlaw, T M; Boyce, J A (2012) Cysteinyl leukotriene receptors, old and new; implications for asthma. Clin Exp Allergy 42:1313-20
Adachi, Roberto; Krilis, Steven A; Nigrovic, Peter A et al. (2012) Ras guanine nucleotide-releasing protein-4 (RasGRP4) involvement in experimental arthritis and colitis. J Biol Chem 287:20047-55

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