Individuals with aspirin exacerbated respiratory disease (AERD) demonstrate selective airway hyperresponsiveness to leukotriene (LT)E4 by unclear mechanisms. This Project tests the role of a novel LTE4 receptor, GPR99, in mediating the potent effects of LTE4 on cutaneous and pulmonary vascular leak in mice, and in mediating Th2-dominated pulmonary inflammaton in a model of dust mite-induced pulmonary pathology by a pathway involving platelets, P2Y12 receptors, and prostanoids. We found that mice lacking both CysLT1R and CysLT2R (Cysltr1/Cysltr2-/- mice) show markedly increased and prolonged vascular permeability responses to intradermally administered LTE4 relative to wild-type (WT) controls, as well as an enhanced pulmonary vascular leak in response to LTE4. Cysltr1/Cysltr2-/- mice also show cutaneous and pulmonary vascular leak to LTC4 and LTD4 that are equivalent to those in WT mice. Moreover, Cysltr1/Cysltr2-/- mice show a markedly enhanced and prolonged vascular permeability response in IgE-dependent PCA, indicating that CysLTER mediates ear swelling occurring in response to the cysteinyl leukotrienes (cys-LTs) released by activated mast cells. Finally, intranasal sensitization and challenge with house dust mite extract elicits substantial cys-LT-dependent pulmonary inflammation in Cysltr1/Cysltr2-/- mice, implying that cys-LT-driven immune cell functions that lead to a Th2 cytokine profile and pulmonary eosinophilia can occur independently of CysLT1R or CysLT2R. We have identified GPR99 as a candidate receptor for LTE4 based on preliminary in vitro studies.
Aim 1 is to further characterize GPR99 in vitro and to generate the deficient strains needed to prove that GPR99 is the LTE4-specific receptor that mediates vascular and cellular innate and adaptive immune responses in mice lacking CysLT1R and CysLT2R.
Aim 2 is to determine the contribution of GPR99 to the cys-LT-dependent mast cell-mediated vascular leakage in the skin of Cysltr1/Cysltr2-/- mice.
Aim 3 is to determine the contribution of GPR99 to the cys-LT-dependent allergen-induced Th2 cell mediated pulmonary eosinophilic inflammation in Cysltr1/Cysltr2-/- mice. We will also determine the expression of GPR99 in cells from individuals with AERD and aspirin-tolerant controls.
Leukotriene (LT) E4 is implicated in aspirin-exacerbated respiratory disease. This project seeks to identify the receptor for LTE4 and to determine how the receptor contributes to the diseases process. Findings should provide new therapeutic strategy to this severe form of asthma.
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