IL-33-Mediated Mast Cell and Eosinophil Function Requires Isoprenylation

Jason R Burchett¹Aditya Kotha¹Destiny T davis¹Kaitlyn Jackson¹Jordan M Dailey²Tania D Maldonado¹Tamara T Haque³Zakaria Hussain¹John M Ching¹Pamela Guerrerio⁴Said M Sebti¹John Joseph Ryan^1*

• ¹Virginia Commonwealth University, Richmond, United States
• ²University of Michigan, Ann Arbor, United States
• ³Indiana University Indianapolis, Indianapolis, United States
• ⁴National Institute of Allergy and Infectious Diseases, Bethesda, United States

Allergic disease is a common and symptomatically heterogeneous group of inflammatory disorders marked by overactive Th2 and mast cell (MC) responses along with eosinophil infiltration. Treatment options require continual assessment due to breakthrough symptoms on standard regimens. One approach to improved therapy is drug repurposing. Our lab previously showed that cholesterol-lowering statin drugs can suppress IgE-mediated mast cell function by inhibiting protein isoprenylation, a pathway using cholesterol biosynthesis intermediates. In addition to IgE, mast cells are activated by the alarmin IL-33, released by epithelial cells after contact with cellular stressors. We hypothesized that IL-33-mediated mast cell function can be inhibited by disrupting isoprenylation via statins or the dual farnesyltransferase (FT) and geranylgeranyltransferase-1 inhibitor, FGTI-2734. We show simvastatin and FGTI-2734 suppressed IL-33-mediated cytokine protein and mRNA production in primary mouse mast cells from the C57BL/6 strain. Simvastatin effects were lost on mast cells from the 129/SvJ strain and were inconsistent among primary human mast cells. In contrast, FGTI-2734 inhibited IL-33-induced cytokine production by mast cells on the 129/SvJ strain and among human donors. Simvastatin and FGTI-2734 also inhibited IL-33-induced cytokine production and chemokine-induced migration of C57BL/6 primary eosinophils. Simvastatin and FGTI-2734 had no effect on expression of the IL-33 receptor, ST2, suggesting that inhibition occurs at a step in IL-33 signaling. Importantly, FGTI-2734 significantly reduced eosinophil and neutrophil influx in a model of IL-33-induced peritonitis, whereas simvastatin had no effect. These findings indicate that while statins can suppress IL-33-mediated mast cell function, their in vivo efficacy is limited. In contrast, directly targeting FT and GGT-1 is a viable path for IL-33-induced inflammation.