The central focus of this collaborative and synergic program project directed to the developmental biology and function of the mast cell (MC) and the regulation and function of the cysteinyl leukotriene-generating pathway now intersects with both innate and adaptive immune inflammation. The ongoing approach is broadened by studies of ligands for culture-derived human MCs (hMCs), of mice with targeted disruptions of the key proteins involved in expression or function of the effector pathways of allergic/asthmatic inflammation, and by a capacity to compare cells from asthmatic donors with those from normal individuals to see dysregulated responses. The leukocyte immunoglobulin-like receptor (LIR) family is represented by an activating LIR7 and an inhibitory LIR3 on basophils, eosinophils, neutrophils, and MC progenitors (MCp). Coligation to activate LIR7 releases preformed mediators, cysteinyl leukotrienes (cysLTs), and cytokines from eosinophils and simultaneous coligation of LIR3 on basophils prevent this response. Thus, Project 1 seeks dysregulation of this innate pathway at the expression and function levels for particular effector cells of patients with chronic asthma. The recognition that lysophosphatidic acid (LPA) at its physiologic concentration in the presence of lineage-directed cytokines not only replaces serum, but also drives proliferation and maturation of cord blood progenitors into a constitutive phenotype reveals a possible homeostatic signal for the perivascular MC with potential for inflammation-based amplification. The high homology of the three recognized LPA receptors (LPARs) between human and mouse suggests that the ligand can be studied for cutaneous and pulmonary effects in the mouse strains with targeted disruptions initially assessed in the LPA1R null strain in Project 2. In Project 3, the generation of LTC4 synthase (LTC4S) and cysteinyl leukotriene 1 receptor (CysLT1R) null strains, the CysLT2R null strain under development, and a strain transgenic for the human LTC4S gene allows assessment of the cysLT pathway products in models of acute and chronic immunologic pulmonary injury. The finding that IL-4 induction of LTC4S observed with culture-derived hMCs can be replicated with mouse MCs allows dissection of the regulatory signals using null strains. The transendothelial movement and migration of MCp essential to their tissue-based distribution, maturation, and phenotypic expression requires (_4J37 and CXCR2 for homing to intestine but not lung. In Project 4, a model of aerosol antigen-induced pulmonary and intestinal inflammation will again use null strains and blocking mAbs to reveal the common or unique pathways required for expansion of the MCp pool in each organ. Taken together, these studies will provide new information on the tonic control of effect or cell functions by competing LIRs, on the innate regulation of the MC phenotype by serum LPA, on the regulated expression of the MC LTC4S gene, and on the tissue-specific homing and recruitment of MCp for distribution and phenotypic maturation.
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