@article{mackey_moeser_2022, title={Sex Differences in Mast Cell-Associated Disorders: A Life Span Perspective}, volume={14}, ISSN={["1943-0264"]}, DOI={10.1101/cshperspect.a039172}, abstractNote={Mast cells are critical innate immune effectors located throughout the body that are crucial for host defense mechanisms via orchestrating immune responses to a variety of host and environmental stimuli necessary for survival. The role of mast cells in brain development and behavior, meningeal function, and stress-related disorders has also been increasingly recognized. While critical for survival and development, excessive mast cell activation has been linked with an increasing number of inflammatory, stress-associated, and neuroimmune disorders including allergy/anaphylaxis, autoimmune diseases, migraine headache, and chronic pain disorders. Further, a strong sex bias exists for mast cell-associated diseases with females often at increased risk. Here we review sex differences in human mast cell-associated diseases and animal models, and the underlying biological mechanisms driving these sex differences, which include adult gonadal sex hormones as well the emerging organizational role of perinatal gonadal hormones on mast cell activity and development.}, number={10}, journal={COLD SPRING HARBOR PERSPECTIVES IN BIOLOGY}, author={Mackey, Emily and Moeser, Adam J. J.}, year={2022}, month={Oct} }
 @article{mackey_thelen_bali_fardisi_trowbridge_jordan_moeser_2020, title={Perinatal androgens organize sex differences in mast cells and attenuate anaphylaxis severity into adulthood}, volume={117}, ISSN={["0027-8424"]}, DOI={10.1073/pnas.1915075117}, abstractNote={SignificanceMast cell (MC)-associated disorders exhibit a sex bias, with females at increased risk. While attention has been directed to adult sex hormones as a mechanism for disease risk between the sexes, epidemiological evidence clearly shows that these same sex biases also exist in prepubertal children, thus challenging this concept. Here, we show that perinatal, but not adult gonadal, androgens play a protective role in MC-mediated anaphylaxis severity into adulthood. We propose that perinatal androgens mediate their protective effects via programming of bone marrow MC precursors to exhibit reduced granule histamine and release. These findings shift attention to perinatal life as a critical period for potential interventions to mitigate MC-associated disease risk across the lifespan in males and females.}, number={38}, journal={PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA}, author={Mackey, Emily and Thelen, Kyan M. and Bali, Vedrana and Fardisi, Mahsa and Trowbridge, Madalyn and Jordan, Cynthia L. and Moeser, Adam J.}, year={2020}, month={Sep}, pages={23751–23761} }
 @article{belcher_cline_conley_groeters_jefferson_law_mackey_suen_williams_dixon_et al._2019, title={Endocrine Disruption and Reproductive Pathology}, volume={47}, ISSN={["1533-1601"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85076490433&partnerID=MN8TOARS}, DOI={10.1177/0192623319879903}, abstractNote={ During the past 20 years, investigations involving endocrine active substances (EAS) and reproductive toxicity have dominated the landscape of ecotoxicological research. This has occurred in concert with heightened awareness in the scientific community, general public, and governmental entities of the potential consequences of chemical perturbation in humans and wildlife. The exponential growth of experimentation in this field is fueled by our expanding knowledge into the complex nature of endocrine systems and the intricacy of their interactions with xenobiotic agents. Complicating factors include the ever-increasing number of novel receptors and alternate mechanistic pathways that have come to light, effects of chemical mixtures in the environment versus those of single EAS laboratory exposures, the challenge of differentiating endocrine disruption from direct cytotoxicity, and the potential for transgenerational effects. Although initially concerned with EAS effects chiefly in the thyroid glands and reproductive organs, it is now recognized that anthropomorphic substances may also adversely affect the nervous and immune systems via hormonal mechanisms and play substantial roles in metabolic diseases, such as type 2 diabetes and obesity. }, number={8}, journal={TOXICOLOGIC PATHOLOGY}, author={Belcher, Scott M. and Cline, J. Mark and Conley, Justin and Groeters, Sibylle and Jefferson, Wendy N. and Law, Mac and Mackey, Emily and Suen, Alisa A. and Williams, Carmen J. and Dixon, Darlene and et al.}, year={2019}, month={Dec}, pages={1049–1071} }
 @article{d'costa_ayyadurai_gibson_mackey_rajput_sommerville_wilson_li_kubat_kumar_et al._2019, title={Mast cell corticotropin-releasing factor subtype 2 suppresses mast cell degranulation and limits the severity of anaphylaxis and stress-induced intestinal permeability}, volume={143}, ISSN={["1097-6825"]}, DOI={10.1016/j.jaci.2018.08.053}, abstractNote={Psychological stress and heightened mast cell (MC) activation are linked with important immunologic disorders, including allergy, anaphylaxis, asthma, and functional bowel diseases, but the mechanisms remain poorly defined. We have previously demonstrated that activation of the corticotropin-releasing factor (CRF) system potentiates MC degranulation responses during IgE-mediated anaphylaxis and psychological stress through corticotropin-releasing factor receptor subtype 1 (CRF1) expressed on MCs.In this study we investigated the role of corticotropin-releasing factor receptor subtype 2 (CRF2) as a modulator of stress-induced MC degranulation and associated disease pathophysiology.In vitro MC degranulation assays were performed with bone marrow-derived mast cells (BMMCs) derived from wild-type (WT) and CRF2-deficient (CRF2-/-) mice and RBL-2H3 MCs transfected with CRF2-overexpressing plasmid or CRF2 small interfering RNA. In vivo MC responses and associated pathophysiology in IgE-mediated passive systemic anaphylaxis and acute psychological restraint stress were measured in WT, CRF2-/-, and MC-deficient KitW-sh/W-sh knock-in mice.Compared with WT mice, CRF2-/- mice exhibited greater serum histamine levels and exacerbated IgE-mediated anaphylaxis and colonic permeability. In addition, CRF2-/- mice exhibited increased serum histamine levels and colonic permeability after acute restraint stress. Experiments with BMMCs and RBL-2H3 MCs demonstrated that CRF2 expressed on MCs suppresses store-operated Ca2+ entry signaling and MC degranulation induced by diverse MC stimuli. Experiments with MC-deficient KitW-sh/W-sh mice systemically engrafted with WT and CRF2-/- BMMCs demonstrated the functional importance of MC CRF2 in modulating stress-induced pathophysiology.MC CRF2 is a negative global modulator of stimuli-induced MC degranulation and limits the severity of IgE-mediated anaphylaxis and stress-related disease pathogenesis.}, number={5}, journal={JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY}, author={D'Costa, Susan and Ayyadurai, Saravanan and Gibson, Amelia J. and Mackey, Emily and Rajput, Mrigendra and Sommerville, Laura J. and Wilson, Neco and Li, Yihang and Kubat, Eric and Kumar, Ananth and et al.}, year={2019}, month={May}, pages={1865-+} }
 @article{pohl_medland_mackey_edwards_bagley_dewilde_williams_moeser_2017, title={Early weaning stress induces chronic functional diarrhea, intestinal barrier defects, and increased mast cell activity in a porcine model of early life adversity}, volume={29}, ISSN={["1365-2982"]}, DOI={10.1111/nmo.13118}, abstractNote={AbstractBackgroundEarly life adversity (ELA) is a risk factor for development of gastrointestinal disorders later in life. The underlying mechanisms through which ELA and sex interact to influence disease susceptibility remains poorly understood.MethodsUtilizing a porcine early weaning stress (EWS) model to mimic ELA, we investigated the long‐term effects of EWS on functional diarrhea, ileal permeability, mast cell activity and mast cell relationship with enteric ganglia.Key ResultsJuvenile and adult EWS pigs exhibited chronic, functional diarrhea (EWS 43.6% vs late wean control(LWC) 4.8%, P<.0001), increased intestinal permeability (2 fold increase EWS vs LWC, P<.0001), and mast cell numbers (at 7 weeks and 20 weeks ~1.6 fold increase EWS vs LWC, P<.05). Compared with EWS male castrates (Male‐C), females EWS pigs exhibited more frequent diarrhea (58.8% vs 29.9%, P=.0016), and increased intestinal permeability (1‐2 fold higher in EWS females, P<.001). Increased mast cell numbers and their enhanced co‐localization with neuronal ganglia were observed in both Male‐C and female EWS pigs; however, female pigs exhibited greater release of mast cell tryptase upon activation with c48/80 (~1.5 fold increase, P<.05), compared with Male‐C pigs.Conclusions and InferencesThese data demonstrate that pigs exposed to ELA exhibit increased vulnerability to functional diarrhea, intestinal permeability and mast cell activity. Further, these studies also showed that EWS female and Male‐C pigs exhibited dimorphic responses to EWS with female piglets exhibited greater susceptibility and severity of diarrhea, intestinal permeability and mast cell tryptase release. Together, these findings mimic some of the key pathophysiologic findings in human functional GI disorders functional gastrointestinal disorders (FGIDs) suggesting that the EWS porcine model could be a valuable preclinical translational model for FGID research associated with ELA.}, number={11}, journal={NEUROGASTROENTEROLOGY AND MOTILITY}, author={Pohl, C. S. and Medland, J. E. and Mackey, E. and Edwards, L. L. and Bagley, K. D. and DeWilde, M. P. and Williams, K. J. and Moeser, A. J.}, year={2017}, month={Nov} }
 @article{ayyadurai_gibson_d'costa_overman_sommerville_poopal_mackey_li_moeser_2017, title={Frontline Science: Corticotropin-releasing factor receptor subtype 1 is a critical modulator of mast cell degranulation and stress-induced pathophysiology}, volume={102}, ISSN={["1938-3673"]}, DOI={10.1189/jlb.2hi0317-088rr}, abstractNote={Abstract
               Life stress is a major risk factor in the onset and exacerbation of mast cell–associated diseases, including allergy/anaphylaxis, asthma, and irritable bowel syndrome. Although it is known that mast cells are highly activated upon stressful events, the mechanisms by which stress modulates mast cell function and disease pathophysiology remains poorly understood. Here, we investigated the role of corticotropin-releasing factor receptor subtype 1 (CRF1) in mast cell degranulation and associated disease pathophysiology. In a mast cell–dependent model of IgE-mediated passive systemic anaphylaxis (PSA), prophylactic administration of the CRF1-antagonist antalarmin attenuated mast cell degranulation and hypothermia. Mast cell–deficient KitW-sh/W-sh mice engrafted with CRF1−/− bone marrow–derived mast cells (BMMCs) exhibited attenuated PSA-induced serum histamine, hypothermia, and clinical scores compared with wild-type BMMC-engrafted KitW-sh/W-sh mice. KitW-sh/W-sh mice engrafted with CRF1−/− BMMCs also exhibited suppressed in vivo mast cell degranulation and intestinal permeability in response to acute restraint stress. Genetic and pharmacologic experiments with murine BMMCs, rat RBL-2H3, and human LAD2 mast cells demonstrated that although CRF1 activation did not directly induce MC degranulation, CRF1 signaling potentiated the degranulation responses triggered by diverse mast cell stimuli and was associated with enhanced release of Ca2+ from intracellular stores. Taken together, our results revealed a prominent role for CRF1 signaling in mast cells as a positive modulator of stimuli-induced degranulation and in vivo pathophysiologic responses to immunologic and psychologic stress.}, number={6}, journal={JOURNAL OF LEUKOCYTE BIOLOGY}, author={Ayyadurai, Saravanan and Gibson, Amelia J. and D'Costa, Susan and Overman, Elizabeth L. and Sommerville, Laura J. and Poopal, Ashwini C. and Mackey, Emily and Li, Yihang and Moeser, Adam J.}, year={2017}, month={Dec}, pages={1299–1312} }
 @article{mackey_ayyadurai_pohl_costa_li_moeser_2016, title={Sexual dimorphism in the mast cell transcriptome and the pathophysiological responses to immunological and psychological stress}, volume={7}, ISSN={["2042-6410"]}, DOI={10.1186/s13293-016-0113-7}, abstractNote={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.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.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.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.}, journal={BIOLOGY OF SEX DIFFERENCES}, author={Mackey, Emily and Ayyadurai, Saravanan and Pohl, Calvin S. and Costa, Susan D' and Li, Yihang and Moeser, Adam J.}, year={2016}, month={Nov} }