Role of phosphoinositide 3-kinases in mast cell activation

Mast cells are primary effector cells in allergy and chronic inflammation. Class IB (PI3Kγ)
and class IA (PI3Kδ) PI3K have been shown to play major roles in mast cell activation:
antigen/IgE stimulation triggers autocrine/paracrine activation of mast cells through G
protein-coupled receptors (GPCRs) and PI3Kγ, e.g. by adenosine through the A3 adenosine
receptor. PI3Kδ acts downstream of c-kit to promote mast cell growth and differentiation.
Presently, data concerning the relative importance of PI3Kγ and PI3Kδ are controversial.
Here we investigate the role of PI3Kγ and PI3Kδ during mast cell activation and allergic
responses. From blood to tissues, we demonstrate that PI3Kγ is a major player in mast cell
adhesion to endothelia involving α4β1 integrin whereas adhesion to fibronectin is mediated
by α5β1 integrin. VCAM-1 and ICAM-1 upregulation and mast cell-derived TNF-α-
mediated activation of endothelia also require functional PI3Kγ. Genetic and pharmacologic
approaches confirm the role of PI3Kδ in stem factor signaling (SCF) signaling. However,
IgE/antigen signaling and mast cell degranulation are driven by PI3Kγ. Finally, in vivo mast
cell recruitment as well as passive cutaneous anaphylaxis experiments are severely impaired
by absence or pharmacological inhibition of PI3Kγ. Altogether, modulation of PI3Kγ and
TNF-α affect mast cell function in crucial phases, rendering them appropriated targets for
allergic diseases.