Loss of isoprenylation significantly reduces IgE mediated mast cell activation

Abstract

Abstract Allergic disease is the 6th leading cause of chronic illness in the US and accounts for billions of dollars in healthcare costs annually. Mast cells are tissue resident innate immune cells linked to allergic disease and activated by IgE and other ligands. Upon activation they release histamine, cytokines, chemokines, proteases, and lipid mediators evoking allergic symptoms. New ways of targeting mast cells could greatly benefit allergic disease therapy. Previous findings showed repurposing of statin drugs, such as Fluvastatin, reduced allergic symptoms in vitro and in vivo. We found that Fluvastatin suppresses IgE-mediated mast cell activation by inhibiting isoprenylation of proteins. However, statin effects were dependent on genetic background. To avert genetic background dependency, we tested the hypothesis that a dual farnesyl and geranylgeranyl transferase inhibitor (FGTI 2734) would suppress allergic disease withoutgenetic background limitations. We show that FGTI 2734 reduced IgE-mediated degranulation and cytokine production by bone marrow derived mast cells from multiple genetic backgrounds. Similarly, FGTI 2734 also suppressed IgE-mediated anaphylaxis on multiple genetic backgrounds. These in vivo effects extended to an allergic asthma model, in which FGTI 2734 inhibited pulmonary inflammation. Finally, we show that FGTI-2734 can significantly reduce IgE-induced cytokine production from human skin mast cells. These data show that dual farnesyl and geranylgeranyl transferase inhibitors may be an effective therapeutic treatment for mast cell-associated diseases. Supported by NIH (1RO1AI101153)