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Papers by Amelia Gibson

Journal of Immunology, 2017

Psychological stress triggers mast cell (MC) activation and is a major risk factor in the onset a... more Psychological stress triggers mast cell (MC) activation and is a major risk factor in the onset and exacerbation of MC-associated disorders including allergy/anaphylaxis, irritable bowel syndrome, and autoimmune diseases. The mechanisms by which stress modulates MC function and disease susceptibility is poorly understood. Our previous studies showed that corticotropin releasing factor receptor 1 (CRF 1 ) signaling potentiated stress-induced MC degranulation. Here we utilized CRF 2 deficient (CRF 2 −/− ) mice and MCs to define the in vivo and in vitro biological importance of CRF receptor subtype 2, CRF 2 . Compared with WT mice, CRF 2 −/− mice exhibited greater serum histamine levels following restraint stress (RS) (by 143%) and IgE-mediated passive systemic anaphylaxis (PSA) (by 415%). The heightened response was greater in CRF 2 −/− females compared with males. CRF 2 −/− mice exhibited greater RS-induced and PSA-induced elevations in intestinal permeability compared to WT mice. Bo...

Journal of Leukocyte Biology, 2017

Life stress is a major risk factor in the onset and exacerbation of mast cell-associated diseases... more 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 (CRF) 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 CRF-antagonist antalarmin attenuated mast cell degranulation and hypothermia. Mast cell-deficient mice engrafted with CRF bone marrow-derived mast cells (BMMCs) exhibited attenuated PSA-induced serum histamine, hypothermia, and clinical scores compared with wild-type BMMC-engrafted mice. mice engrafted with CRF 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 CRF activation did not directly induce MC degranulation, CRF signaling potentiated the degranulation responses triggered by diverse mast cell stimuli and was associated with enhanced release of Ca from intracellular stores. Taken together, our results revealed a prominent role for CRF signaling in mast cells as a positive modulator of stimuli-induced degranulation and in vivo pathophysiologic responses to immunologic and psychologic stress.

Gastroenterology, 2013

in vitro bacterial killing assay was used to determine NK cell cytotoxic activity against C. rode... more in vitro bacterial killing assay was used to determine NK cell cytotoxic activity against C. rodentium. Results: During C. rodentium infection NK cells were recruited to both mucosal and systemic tissues where they expressed a diversity of immune-modulatory factors. In NK cell depleted mice we observed less severe colonic inflammation, which was associated with reduced immune cell recruitment and lower cytokine levels. However, bacterial loads were higher in NK cell depleted mice, and we also observed disseminated systemic infection, when compared to control infected mice. Interestingly, NK cells could also directly kill C. rodentium in vitro. Conclusion: Together these results suggest that NK cells protect the host from prolonged mucosal and systemic infection by contributing direct cytokine and antimicrobial cytotoxic factors, and by providing signals leading to the infiltration and increased activation of other crucial immune populations. This comprehensive anti-infection NK cell response may represent a promising therapeutic focus, particularly for approaches against enteric bacterial infections.

Gastroenterology, 2015

the effect of PHGG on stress mimicked corticotropin-releasing hormone (CRH) induced animal IBS mo... more the effect of PHGG on stress mimicked corticotropin-releasing hormone (CRH) induced animal IBS model. Materials and methods. Six-week-old male Wistar rats were used in this study. Animals were allowed to acclimate to the environment for seven days before initiating the study. Under anesthesia, each rat was implanted stainless steel cannula placed towards the lateral cerebral ventricle. Then rats were divided into two groups of 8 animals each, (1) control group: diet without PHGG, (2) PHGG group: diet with 5% PHGG for seven days. After intracerebroventricular (icv) injection of CRH (10 μg / rat) or saline in each, the condition of stools was checked with a 2-hour fecal pellets output count. Three hours later, rats were sacrificed, and cecal contents were taken out to analyze the microbiota with terminal restriction fragment length polymorphism (T-RFLP). Results. The counts of stools were increased in CRH-treated animals compared to in saline-treated group animals with the control diet. However, in rats in PHGG group with icv of CRH, the numbers of stools were not increased. In PHGG group Clostridium subcluster XIVa, which thought to be products butyric acid and Bifidobacterium cluster were enlarged, but not in the control diet group, then after injection of CRH, Bifidobacterium cluster was decreased. Conclusions. PHGG improved CRH-induced bowel dysmotility and also modulated in the gut microbiota composition which were influenced by CRH administration. Our results indicate that braingut axis is deeply associated with gut microbiota in physiological mechanism in IBS. This study was supported by Japan Science and Technology Agency.

Critical Care Medicine, 2013

Background-Cardiac surgery, especially when employing cardiopulmonary bypass (CPB) and deep hypot... more Background-Cardiac surgery, especially when employing cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA), is associated with systemic inflammatory responses that significantly affect morbidity and mortality. Intestinal perfusion abnormalities have been implicated in such responses, but the mechanisms linking local injury and systemic inflammation remain unclear. Intestinal mast cells (MC) are specialized immune cells that secrete various preformed effectors in response to cellular stress. We hypothesized that MCs are activated in a microenvironment shaped by intestinal ischemia/reperfusion (I/R), and investigated local and systemic consequences in a rat model of DHCA. Methods and Results-Adult rats were cooled to 16-18°C on CPB before instituting DHCA for 45 minutes. Specimens were harvested following rewarming and 2 hours of recovery. Significant intestinal barrier disruption was found, together with macro-and microscopic evidence of I/R injury in ileum and colon but not in lungs or kidneys. Immunofluorescence and toluidine blue staining revealed MC hyperplasia and activation in the gut. Pretreatment with the MC stabilizer cromolyn sodium efficiently blocked MC degranulation and resulted in preserved intestinal morphology and barrier function following DHCA. Furthermore, cromolyn sodium treatment dramatically reduced intestinal neutrophil influx and systemic release of various proinflammatory cytokines.

The FASEB Journal, 2012

Psychological stress is gaining recognition as an important predisposing or inciting factor in th... more Psychological stress is gaining recognition as an important predisposing or inciting factor in the development of gastrointestinal disease. The shift from a protective response intended to maintain homeostasis to one that results in profound consequences and the development of disease is unclear. The stress response is mediated by corticotropin-releasing factor (CRF) that may be released both centrally and peripherally. The bi-directional communication between the brain and gut serves as the link between stress perception and gastrointestinal function. Mast cells have been identified as important mediators of the braingut axis, and previous research has demonstrated that intestinal mast cells play a critical role in mediating stress-induced gastrointestinal dysfunction although the mechanism remains unclear. Mast cells have been shown to express both CRF receptor subtypes, CRF 1 and CRF 2 , and can be activated through binding of either receptor. However, the influence of CRF 1 and CRF 2 on mast cell function during the stress response is yet to be elucidated. Here we demonstrate a dichotomous role of CRF receptor subtypes in mast cell activation in response to psychological stress. Furthermore, we have identified a novel protective role for mast cell CRF 2 in modulating stress-induced intestinal permeability. Mast cell-deficient mice repleted with CRF 1-/-bone marrow-derived mast cells (BMMCs) were completely protected from stress-induced increases in intestinal permeability; whereas, mice repleted with CRF 2-/v TABLE OF CONTENTS LIST OF FIGURES .

Journal of Allergy and Clinical Immunology

Background: Psychological stress and heightened MC activation are linked with important immunolog... more Background: Psychological stress and heightened MC activation are linked with important immunological 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, via CRF receptor subtype (CRF 1) expressed on MCs. Objective: In this study, we investigated the role of CRF receptor subtype (CRF) as a modulator of stress-induced MC degranulation and associated disease pathophysiology. Methods: In vitro MC degranulation assays were performed with bone marrow derived MCs (BMMCs) derived from WT and CRF 2-deficient (CRF 2-/-) mice and RBL-2H3 MCs transfected with CRF 2-overexpressing plasmid or CRF 2-siRNA. In vivo MC responses and associated pathophysiology in IgE-mediated passive systemic anaphylaxis (PSA) and acute psychological restraint stress were measured in WT, CRF 2-/-, and MC-deficient Kit W-sh/W-sh knock-in mice. Results: Compared with WT mice, CRF 2-/exhibited heightened serum histamine levels and exacerbated PSA-induced anaphylactic responses and colonic permeability. In addition, CRF 2-/mice exhibited increased serum histamine and colonic permeability following acute restraint stress. Experiments with BMMCs and RBL-2H3 MCs demonstrated that CRF 2 expressed on MCs suppresses store-operated Ca 2+ entry (SOCE) signaling and MC

PLoS ONE, 2013

Background and Aims: The clinical onset and severity of intestinal disorders in humans and animal... more Background and Aims: The clinical onset and severity of intestinal disorders in humans and animals can be profoundly impacted by early life stress. Here we investigated the impact of early weaning stress in pigs on intestinal physiology, clinical disease, and immune response to subsequent challenge with enterotoxigenic F18 E. coli (ETEC). Methodology: Pigs weaned from their dam at 16 d, 18 d, and 20 d of age were given a direct oral challenge of F18 ETEC at 26 d of age. Pigs were monitored from days 0 to 4 post-infection for clinical signs of disease. On Day 4 post-ETEC challenge, ileal barrier function, histopathologic and inflammatory cytokine analysis were performed on ileal mucosa. Results: Early weaned pigs (16 d and 18 d weaning age) exhibited a more rapid onset and severity of diarrhea and reductions in weight gain in response to ETEC challenge compared with late weaned pigs (20 d weaning age). ETEC challenge induced intestinal barrier injury in early weaned pigs, indicated by reductions in ileal transepithelial electrical resistance (TER) and elevated FD4 flux rates, in early weaned pig ileum but not in late weaned pigs. ETEC-induced marked elevations in IL-6 and IL-8, neutrophil recruitment, and mast cell activation in late-weaned pigs; these responses were attenuated in early weaned pigs. TNF levels elevated in ETEC challenged ileal mucosa from early weaned pigs but not in other weaning age groups. Conclusions: These data demonstrate the early weaning stress can profoundly alter subsequent immune and physiology responses and clinical outcomes to subsequent infectious pathogen challenge. Given the link between early life stress and gastrointestinal diseases of animals and humans, a more fundamental understanding of the mechanisms by which early life stress impacts subsequent pathophysiologic intestinal responses has implications for the prevention and management of important GI disorders in humans and animals.