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

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ABSTRACT

Background: Biological 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.

Methods: Twelve-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.

Results: Sexually 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.

Conclusions: These 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 material: The online version of this article (doi:10.1186/s13293-016-0113-7) contains supplementary material, which is available to authorized users.

No MeSH data available.


Influence of the estrous cycle on serum histamine response and tissue MC histamine content and number. a After experiencing 30 min of RS, serum histamine levels were similar between female mice in all stages of the estrous cycle. b The total histamine content of mouse female pMCs was similar at each stage of the estrous cycle. c During proestrus and estrus, female mice had higher numbers of pMCs than male mice. Values represent mean ± SE. *P < 0.05 vs. males
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Fig7: Influence of the estrous cycle on serum histamine response and tissue MC histamine content and number. a After experiencing 30 min of RS, serum histamine levels were similar between female mice in all stages of the estrous cycle. b The total histamine content of mouse female pMCs was similar at each stage of the estrous cycle. c During proestrus and estrus, female mice had higher numbers of pMCs than male mice. Values represent mean ± SE. *P < 0.05 vs. males

Mentions: The estrous cycle, characterized by fluctuations of ovarian steroid hormones, has been shown to influence MC density and phenotype in multiple rodent tissues [37, 38]. Therefore, we sought to evaluate whether the estrous cycle was influencing the sexually dimorphic MC pathophysiology and phenotype demonstrated in the present study. Serum histamine levels following RS did not differ between female mice in different stages of the estrous cycle (Fig. 7a). Similarly, no differences were found in histamine content of pMCs in female mice with regard to the estrous cycle (Fig. 7b). Interestingly, a mildly increased number of pMCs was found in female mice in proestrus and estrus in comparison to Met/Diestrus, similar to findings previously discovered in rat mammary gland tissue (F(3,14) = 4.303, p = 0.0239; Fig. 7c) [39].Fig. 7


Sexual dimorphism in the mast cell transcriptome and the pathophysiological responses to immunological and psychological stress
Influence of the estrous cycle on serum histamine response and tissue MC histamine content and number. a After experiencing 30 min of RS, serum histamine levels were similar between female mice in all stages of the estrous cycle. b The total histamine content of mouse female pMCs was similar at each stage of the estrous cycle. c During proestrus and estrus, female mice had higher numbers of pMCs than male mice. Values represent mean ± SE. *P < 0.05 vs. males
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Related In: Results  -  Collection

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Fig7: Influence of the estrous cycle on serum histamine response and tissue MC histamine content and number. a After experiencing 30 min of RS, serum histamine levels were similar between female mice in all stages of the estrous cycle. b The total histamine content of mouse female pMCs was similar at each stage of the estrous cycle. c During proestrus and estrus, female mice had higher numbers of pMCs than male mice. Values represent mean ± SE. *P < 0.05 vs. males
Mentions: The estrous cycle, characterized by fluctuations of ovarian steroid hormones, has been shown to influence MC density and phenotype in multiple rodent tissues [37, 38]. Therefore, we sought to evaluate whether the estrous cycle was influencing the sexually dimorphic MC pathophysiology and phenotype demonstrated in the present study. Serum histamine levels following RS did not differ between female mice in different stages of the estrous cycle (Fig. 7a). Similarly, no differences were found in histamine content of pMCs in female mice with regard to the estrous cycle (Fig. 7b). Interestingly, a mildly increased number of pMCs was found in female mice in proestrus and estrus in comparison to Met/Diestrus, similar to findings previously discovered in rat mammary gland tissue (F(3,14) = 4.303, p = 0.0239; Fig. 7c) [39].Fig. 7

View Article: PubMed Central - PubMed

ABSTRACT

Background: Biological 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.

Methods: Twelve-week-old C57BL/6 male and female mice were exposed to immunological stress (2&nbsp;h of IgE-mediated passive systemic anaphylaxis (PSA)) or psychological stress (1&nbsp;h of restraint stress (RS)) and&nbsp;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.

Results: Sexually 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 &beta;-hexosaminidase, histamine, tryptase, and TNF-&alpha; 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.

Conclusions: These 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 material: The online version of this article (doi:10.1186/s13293-016-0113-7) contains supplementary material, which is available to authorized users.

No MeSH data available.