Sexual dimorphism in the mast cell transcriptome and the pathophysiological responses to immunological and psychological stress

Abstract

BackgroundBiological sex plays a prominent role in the prevalence and severity of a number of important stress-related gastrointestinal and immune-related diseases including IBS and allergy/anaphylaxis. Despite the establishment of sex differences in these diseases, the underlying mechanisms contributing to sex differences remain poorly understood. The objective of this study was to define the role of biological sex on mast cells (MCs), an innate immune cell central to the pathophysiology of many GI and allergic disorders.MethodsTwelve-week-old C57BL/6 male and female mice were exposed to immunological stress (2 h of IgE-mediated passive systemic anaphylaxis (PSA)) or psychological stress (1 h of restraint stress (RS)) and temperature, clinical scores, serum histamine, and intestinal permeability (for RS) were measured. Primary bone marrow-derived MCs (BMMCs) were harvested from male and female mice and analyzed for MC degranulation, signaling pathways, mediator content, and RNA transcriptome analysis.ResultsSexually dimorphic responses were observed in both models of PSA and RS and in primary MCs. Compared with male mice, female mice exhibited increased clinical scores, hypothermia, and serum histamine levels in response to PSA and had greater intestinal permeability and serum histamine responses to RS. Primary BMMCs from female mice exhibited increased release of β-hexosaminidase, histamine, tryptase, and TNF-α upon stimulation with IgE/DNP and A23187. Increased mediator release in female BMMCs was not associated with increased upstream phospho-tyrosine signaling pathways or downstream Ca2+ mobilization. Instead, increased mediator release in female MCs was associated with markedly increased capacity for synthesis and storage of MC granule-associated immune mediators as determined by MC mediator content and RNA transcriptome analysis.ConclusionsThese results provide a new understanding of sexual dimorphic responses in MCs and have direct implications for stress-related diseases associated with a female predominance and MC hyperactivity including irritable bowel syndrome, allergy, and anaphylaxis.Electronic supplementary materialThe online version of this article (doi:10.1186/s13293-016-0113-7) contains supplementary material, which is available to authorized users.

Early weaning stress induces chronic functional diarrhea, intestinal barrier defects, and increased mast cell activity in a porcine model of early life adversity

“…Given the present findings and our previous studies in mice and rats, female mast cells possess the ability to synthesize, store and release more mast cell mediators compared with male MCs (48), the enhanced tryptase release could be a result of increased tryptase content in female EWS mast cells. In addition differences in adult sex hormones, such as increased estrogen in female pigs or reduced androgens in Male-C pigs could have contributed to these changes.…”

“…Therefore, an enhanced release of MC tryptase in EWS females pigs could have artificially reduced the number of mast cells in the intestinal tissues in female pigs. We have previously shown that mast cell tryptase and chymase expression can differ significantly in chronically stressed pigs (54) and that female mast cells obtained from rat and mice contain higher amounts of intracellular mediators at baseline (non-stressed conditions) compared with sexually mature intact males (48) suggesting the composition of mediators in female and male mast cells are different and can change in response to stress.…”

“…In mice, we showed that the elevated mast cell mediator levels and release observed in adult female mice were not influenced by different stages of the estrous cycle. (48)…”

Neuroimmunology and neuroepigenetics in the establishment of sex differences in the brain

“…Mast cell numbers increase in specific brain regions in both male and female rodents when exposed to sexually receptive stimuli of the other sex 63,64 . Furthermore, the transcriptome of peripheral mast cells is markedly different in males and females 65 . Mast cells have not yet been implicated directly in brain sexual differentiation, but, given their involvement in reproductive responses, the potential for such a role is high.…”

Sex-specific differences in transcriptome profiles of brain and muscle tissue of the tropical gar

“…Additionally, these expression differences can lead to skewed disease risk between sexes [19]. Differences in gene expression between sexes has been shown to be relevant in human neurological diseases [15] and immune diseases, such as irritable bowel syndrome and allergy [20]. While gene expression differences between sexes can contribute to disease, there is also evidence that sexually dimorphic gene expression patterns are evolutionarily conserved and therefore also important to phenotypic differences between sexes [21].…”