Tafazzin Modulates Allergen-Induced Mast Cell Inflammatory Mediator Secretion

Allergic inflammatory diseases are a steadily growing health concern. Mast cells, a driving force behind allergic pathologies, modulate metabolic pathways to carry out various functions following IgE-FceRI-mediated activation. Tafazzin (TAZ) is a cardiolipin transacylase that functions to remodel, and thereby mature, cardiolipin, which is important for efficient energy production through oxidative phosphorylation. In this study, we aimed to evaluate the contribution of TAZ in IgE-mediated mast cell activation. Fetal liver-derived mast cells (FLMCs) were differentiated from mice with a doxycycline (dox)-inducible TAZ short hairpin RNA (shRNA) cassette (TAZ shRNA¹/¹) and littermate wild-types (WTs). TAZ knockdown in FLMCs following dox treatment was confirmed by Western blotting (99.1% by day 5), whereas flow cytometry confirmed FLMC phenotype (c-kit⁺ FceRI⁺) and retention of receptor expression post-dox. Five-day dox-treated WT and TAZ shRNA¹/¹ FLMCs were activated via allergen-bound IgE cross-linking of FceRI under stem cell factor potentiation. With dox, and in response to allergen, TAZ shRNA¹/¹ FLMCs displayed a 25% reduction in oxygen consumption and a significant 31% reduction in mast cell degranulation compared with dox-treated WT FLMCs. Secretion of TNF, CCL1, and CCL2 were significantly reduced, with CCL9 also impaired. Notably, gene expression was not impaired for any inflammatory mediator measured. Functionally, this suggests that TAZ is a contributor to mast cell degranulation and inflammatory mediator secretion. Given unimpacted induced gene expression for mediators measured, we propose that TAZ reduction impairs mast cell exocytosis mechanisms.