- 作者：Emilie Collmann ; Thomas Bohnacker ; Romina Marone ; Janet Dawson ; Markus Rehberg ; Rowan Stringer ; Fritz Krombach ; Christoph Burkhart ; Emilio Hirsch ; Gregory J. Hollingworth ; Matthew Thomas ; Matthias P. Wymann
- 关键词：Mast cells ; recruitment ; migration ; phosphoinositide 3-kinase ; anaphylaxis ; inflammation ; allergy
- 刊名：Journal of Allergy and Clinical Immunology
- 出版年：2013
- 出版时间：October, 2013
- 年：2013
- 卷：132
- 期：4
- 页码：959-968
- 全文大小：2137 K
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 PI3K¦Ã or PI3K¦Ä or mice treated with isoform-specific PI3K inhibitors (a novel PI3K¦Ã-specific inhibitor [NVS-PI3-4] and the PI3K¦Ä inhibitor IC87114) were used to monitor IgE-mediated mast cell recruitment, migration, adhesion by means of intravital microscopy, degranulation, TNF-¦Á release, and subsequent endothelial cell activation in?vivo or in bone marrow-derived mast cells.
Results
Functional PI3K¦Ã, but not PI3K¦Ä, was crucial for mast cell accumulation in IgE-challenged skin, TNF-¦Á release from IgE/antigen-stimulated mast cells, and mast cell/endothelial interactions and chemotaxis. PI3K¦Ã-deficient bone marrow-derived mast cells did not adhere to the endothelium in TNF-¦Á-treated cremaster muscle, whereas PI3K¦Ä was not required. Depletion of TNF-¦Á 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.