Mast cells (MCs) are well known for their detrimental effects in the context of allergic disorders. Strategies that limit MC function can therefore have a therapeutic value. Previous studies have shown that
siramesine, a
sigma-2 receptor agonist originally developed as an anti-depressant, can induce cell death in transformed cells through a mechanism involving lysosomal destabilization. Since MCs are remarkably rich in lysosome-like secretory granules we reasoned that MCs might be sensitive to
siramesine. Here we show that murine and human MCs are highly sensitive to
siramesine. Cell death was accompanied by secretory granule permeabilization, as shown by reduced
acridine orange staining and leakage of granule
proteases into the cytosol. Wild type
siramesine-treated MCs underwent cell death with typical signs of apoptosis but MCs lacking
serglycin, a
proteoglycan crucial for promoting the storage of
proteases within MC secretory granules, died predominantly by
necrosis. A dissection of the underlying mechanism suggested that the necrotic phenotype of
serglycin(-/-) cells was linked to defective
Poly(ADP-ribose) polymerase-1 degradation. In vivo,
siramesine treatment of mice caused a depletion of the MC populations of the peritoneum and skin. The present study shows for the first time that MCs are highly sensitive to apoptosis induced by
siramesine and introduces the possibility of using
siramesine as a therapeutic agent for treatment of MC-dependent disease.