Transient targeting of phosphoinositide 3-kinase acts as a roadblock in mast cells' route to allergy

• Published in: Journal of allergy and clinical immunology 2013-10, Vol.132 (4), p.959-968
• Main Authors: Collmann, Emilie, PhD, Bohnacker, Thomas, PhD, Marone, Romina, PhD, Dawson, Janet, PhD, Rehberg, Markus, PhD, Stringer, Rowan, PhD, Krombach, Fritz, PhD, Burkhart, Christoph, PhD, Hirsch, Emilio, PhD, Hollingworth, Gregory J., PhD, Thomas, Matthew, PhD, Wymann, Matthias P., PhD
• Format: Article
• Language: English
• Subjects: Allergies; allergy; Allergy and Immunology; anaphylaxis; Anaphylaxis - drug therapy; Anaphylaxis - immunology; Anaphylaxis - metabolism; Animals; Anti-Allergic Agents - therapeutic use; Antigens; Biological and medical sciences; Cell Degranulation - immunology; Cell Movement; Chronic illnesses; Class Ib Phosphatidylinositol 3-Kinase - genetics; Class Ib Phosphatidylinositol 3-Kinase - metabolism; Drug dosages; Endothelial Cells - immunology; Enzyme Inhibitors - therapeutic use; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Humans; Hypersensitivity - drug therapy; Hypersensitivity - immunology; Hypersensitivity - metabolism; Immunopathology; inflammation; Kinases; Mast cells; Mast Cells - immunology; Mast Cells - metabolism; Medical sciences; Mice; Mice, Inbred C57BL; migration; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; phosphoinositide 3-kinase; Product safety; Proteins; recruitment; Rodents; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2013.03.008

Background Tissue mast cell numbers are dynamically regulated by recruitment of progenitors from the vasculature. It is unclear whether progenitors are recruited during allergic sensitization and whether recruitment promotes allergic responses. Objective We sought to (1) determine the effect of mast cell recruitment on acute allergic responses and (2) to define the role of phosphoinositide 3-kinase (PI3K) isoforms in sequential steps to allergic responses. Methods Gene-targeted mice for PI3Kγ or PI3Kδ or mice treated with isoform-specific PI3K inhibitors (a novel PI3Kγ-specific inhibitor [NVS-PI3-4] and the PI3Kδ inhibitor IC87114) were used to monitor IgE-mediated mast cell recruitment, migration, adhesion by means of intravital microscopy, degranulation, TNF-α release, and subsequent endothelial cell activation in vivo or in bone marrow–derived mast cells. Results Functional PI3Kγ, but not PI3Kδ, was crucial for mast cell accumulation in IgE-challenged skin, TNF-α release from IgE/antigen-stimulated mast cells, and mast cell/endothelial interactions and chemotaxis. PI3Kγ-deficient bone marrow–derived mast cells did not adhere to the endothelium in TNF-α–treated cremaster muscle, whereas PI3Kδ was not required. Depletion of TNF-α blocked IgE-induced mast cell recruitment, which links tissue mast cell–derived cytokine release to endothelial activation and mast cell recruitment. Interference with mast cell recruitment protected against anaphylaxis and was superior to blockage of tissue mast cell degranulation. Conclusions Interference with mast cell recruitment to exacerbated tissues provides a novel strategy to alleviate allergic reactions and surpassed attenuation of tissue mast cell degranulation. This results in prolonged drug action and allows for reduction of drug doses required to block anaphylaxis, an important feature for drugs targeting inflammatory disease in general.