IL-33-mediated mast cell and eosinophil function requires isoprenylation

Area of Science:

• Immunology
• Pharmacology

Background:

• Allergic diseases involve overactive Th2 responses, mast cell (MC) activation, and eosinophil infiltration.
• Current treatments require assessment due to breakthrough symptoms.
• Drug repurposing, like using statins to inhibit protein isoprenylation, is a promising therapeutic avenue.

Purpose of the Study:

• To investigate the potential of inhibiting protein isoprenylation via statins or FGTI-2734 to suppress IL-33-mediated mast cell and eosinophil function.
• To evaluate the efficacy of these inhibitors in vitro and in a murine model of IL-33-induced peritonitis.

Main Methods:

• Stimulated primary mast cells and eosinophils with IL-33 in vitro.
• Inhibited function using simvastatin and FGTI-2734.
• Measured cytokine production, phosphorylation, and eosinophil migration.
• Assessed human mast cells and used a murine model of IL-33-induced peritonitis.

Main Results:

• Simvastatin and FGTI-2734 suppressed IL-33-mediated cytokine production in murine mast cells, but simvastatin showed strain-dependent and inconsistent effects in human cells.
• FGTI-2734 consistently inhibited IL-33-induced cytokine production in mast cells across different strains and human donors.
• Both inhibitors affected IL-33-induced eosinophil responses; FGTI-2734 significantly reduced eosinophil and neutrophil influx in vivo, while simvastatin did not.

Conclusions:

• Targeting farnesyltransferase (FT) and geranylgeranyltransferase-1 (GGT-1) is a viable strategy for treating IL-33-induced inflammation.
• FGTI-2734 demonstrates significant therapeutic potential in reducing allergic inflammatory cell infiltration.