title: Sexual dimorphism in the mast cell transcriptome and the pathophysiological responses to immunological and psychological stress.
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.
authors.affiliation: Gastrointestinal Stress Biology Laboratory, Michigan State University, East Lansing, MI 48824 USA ; Comparative Biomedical Sciences Program, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27603 USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Mackey
authors.affiliation: Gastrointestinal Stress Biology Laboratory, Michigan State University, East Lansing, MI 48824 USA ; Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824 USA.
authors.forename: Saravanan
authors.initials: S
authors.lastname: Ayyadurai
authors.affiliation: Gastrointestinal Stress Biology Laboratory, Michigan State University, East Lansing, MI 48824 USA ; Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824 USA.
authors.forename: Calvin S
authors.initials: CS
authors.lastname: Pohl
authors.affiliation: Department of Medicine, University of North Carolina, Chapel Hill, NC 27599 USA.
authors.forename: Susan
authors.initials: S
authors.lastname: D' Costa
authors.affiliation: Gastrointestinal Stress Biology Laboratory, Michigan State University, East Lansing, MI 48824 USA ; Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824 USA.
authors.forename: Yihang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Gastrointestinal Stress Biology Laboratory, Michigan State University, East Lansing, MI 48824 USA ; Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824 USA ; Neuroscience Program, Michigan State University, East Lansing, MI 48824 USA ; Department of Physiology, Michigan State University, East Lansing, MI 48824 USA.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Moeser
keywords: Allergy; Females; Intestine; Mast cells; Sexual dimorphism; Stress