Androgen Receptor Deficiency Eliminates Sex Differences in Mast Cells

Abstract

Abstract A sex bias exists in mast cell (MC)-associated inflammatory diseases with females at increased risk. Our previous studies demonstrated that MCs exhibit a sexually dimorphic phenotype with male MCs exhibiting significantly reduced concentration and release of MC granule mediators (histamine, serotonin, and proteases) which was associated with reduced severity of anaphylaxis in males. Further, we showed that perinatal androgens are important in organizing male MC sex differences. The mechanisms by which androgens organize MC sex differences remain poorly understood. Utilizing male mice with reduced androgen receptor (AR) expression induced by Cre-LoxP technology (induced TFM; iTfm), we tested the hypothesis that ARs mediate sex differences in MC histamine storage and release, and severity of anaphylaxis. Isolated peritoneal MCs (pMCs) from iTFm male mice exhibited a feminized MC phenotype characterized by a greater level of histamine compared with control male pMCs, but similar to female controls. Following induction of IgE-mediate anaphylaxis in vivo, iTFM male and female pMCs contained lower (n=5–6; P<0.01) histamine contents compared with control males, suggesting enhanced release of histamine. Preliminary results also indicate that iTFm male mice exhibit greater IgE-mediated histamine releases and hypothermia. Experiments with bone marrow derived MCs (BMMCs) showed that IgE-mediated histamine release from iTFm male and female BMMCs was greater (n=5–6; P<0.01) relative to control male BMMCs. Together, these studies demonstrate that sex differences in MC phenotype and function are mediated via Ars and that iTFm mice are a valid model to explore AR-mediated sex differences in MC function and disease pathogenesis. Supported by NIH R01 HD072968, NIH R21 AI140413