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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.


Sexually dimorphic gene expression in BMMCs from C57BL/6 mice. a A total of 8233 genes were found to be differentially expressed between 6-week-old male and female BMMCs using RNA-sequencing technology (Illumina HiSeq 2500) (n = 3). b There were many genes that code for proteins involved in cellular processes and metabolic processes that were upregulated in females compared to males
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Fig8: Sexually dimorphic gene expression in BMMCs from C57BL/6 mice. a A total of 8233 genes were found to be differentially expressed between 6-week-old male and female BMMCs using RNA-sequencing technology (Illumina HiSeq 2500) (n = 3). b There were many genes that code for proteins involved in cellular processes and metabolic processes that were upregulated in females compared to males

Mentions: To gain a more fundamental understanding of why MCs from females contained increased MC granule mediators, we profiled the gene expression patterns in MCs from males and females using RNA sequencing technology (Illumina HiSeq 2500) with RNA extracted from unstimulated BMMCs (1.0 × 107 cells). Remarkably, a total of 8233 genes were expressed differentially between male and female BMMCs (Fig. 8a). This finding demonstrates that, while male and female cells are generally assumed to have very similar autosomal genomes, the expression of the genome can vary immensely between the sexes. The Xist gene, which is exclusively expressed from the inactive X chromosome in females, had the greatest differential expression in females (9.9-fold) [40]. Similarly, two Y chromosome genes, Eif2s3y and Kdm5d, had the greatest differential expression in males (7.6-fold and 8.6-fold, respectively). These results validate RNA sequencing to determine sex-specific differences in BMMCs.Fig. 8


Sexual dimorphism in the mast cell transcriptome and the pathophysiological responses to immunological and psychological stress
Sexually dimorphic gene expression in BMMCs from C57BL/6 mice. a A total of 8233 genes were found to be differentially expressed between 6-week-old male and female BMMCs using RNA-sequencing technology (Illumina HiSeq 2500) (n = 3). b There were many genes that code for proteins involved in cellular processes and metabolic processes that were upregulated in females compared to males
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5120457&req=5

Fig8: Sexually dimorphic gene expression in BMMCs from C57BL/6 mice. a A total of 8233 genes were found to be differentially expressed between 6-week-old male and female BMMCs using RNA-sequencing technology (Illumina HiSeq 2500) (n = 3). b There were many genes that code for proteins involved in cellular processes and metabolic processes that were upregulated in females compared to males
Mentions: To gain a more fundamental understanding of why MCs from females contained increased MC granule mediators, we profiled the gene expression patterns in MCs from males and females using RNA sequencing technology (Illumina HiSeq 2500) with RNA extracted from unstimulated BMMCs (1.0 × 107 cells). Remarkably, a total of 8233 genes were expressed differentially between male and female BMMCs (Fig. 8a). This finding demonstrates that, while male and female cells are generally assumed to have very similar autosomal genomes, the expression of the genome can vary immensely between the sexes. The Xist gene, which is exclusively expressed from the inactive X chromosome in females, had the greatest differential expression in females (9.9-fold) [40]. Similarly, two Y chromosome genes, Eif2s3y and Kdm5d, had the greatest differential expression in males (7.6-fold and 8.6-fold, respectively). These results validate RNA sequencing to determine sex-specific differences in BMMCs.Fig. 8

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 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.