Loss of isoprenylation significantly reduces IgE mediated mast cell activation

Abstract

Abstract Allergic disease a 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. Repurposing statin drugs such as Fluvastatin as a therapeutic treatment of allergic disease showed reduced allergic symptoms using in vitro and in vivo mouse models. We found the Fluvastatin suppresses IgE mediated mast cell activation by inhibiting protein isoprenylation. However, statin suppression is dependent on genetic background. To avert genetic background dependency, we tested the hypothesis that a dual farnesyl and geranylgeranyl transferase inhibitor (FGTI 2734) would consistently suppress mast cell function. We show that FGTI 2734 reduced IgE-mediated degranulation and cytokine production similar to Fluvastatin effects, but maintained efficacy on fluvastatin-resistant genetic backgrounds. FGTI 2734 also suppressed IgE-mediated anaphylaxis in vivo on multiple genetic backgrounds. Finally, inhibition of Ras, a known target of prenylation, can mimic statin effects on IgE-mediated mast cell function. These data support the hypothesis that dual farnesyl and geranylgeranyl transferase inhibitors may be an effective therapeutic treatment for mast cell-associated diseases.