TAK1 contributes to IgE-FcɛRI-mediated calcium mobilization and mast cell degranulation

Abstract Allergic inflammation is an inappropriate immune response, typically triggered by activated mast cells that have been IgE-sensitized to innocuous environmental agents. Allergic inflammatory events can be split into two phases, early and late, initiated by allergen-mediated mast cell activation. The early phase of the allergic response occurs within minutes of an allergen binding and crosslinking IgE-FcɛRI complexes on the surface of a sensitized mast cell. This recognition of a perceived ‘threat’ rapidly induces mast cell activation and subsequent release of pro-inflammatory mediators from preformed granules, a process known as degranulation. We have identified TAK1 as a novel contributor to induced mast cell signaling events and aim to characterize the mechanistic contribution of TAK1 in mast cell degranulation. To this end, we have employed a primary murine model of bone marrow-derived mast cells (BMMC) to examine contributions of TAK1 to IgE-mediated calcium mobilization and degranulation. β-hexosaminidase release assays and Indo-1-based spectrofluorometry demonstrated a significant inhibition (−67% ±1.44 p<0.0001) in degranulation and a reduction in calcium transients (both peak amplitude p<0.01 and area under curve p<0.05) in allergically-activated BMMCs treated with the TAK1 inhibitor, 5Z-7-oxozeaneol (OZ). These results were supported by restoration of normal degranulation with the use of an inactive OZ analog (5Z), whereas an alternative TAK1 inhibitor (AZ) also resulted in degranulation inhibition (−32% ± 2.64 p<0.0001). These results provide novel evidence to support the mechanistic control of mast cell degranulation by TAK1, highlighting its potential as a therapeutic target for allergic pathologies.