Mast Cell CRF2 Suppresses Mast Cell Degranulation and Limits the Severity of Anaphylaxis and Stress-Induced Intestinal Permeability (original) (raw)
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The FASEB Journal, 2012
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 .
Neurogastroenterology and Motility, 2004
releasing-factor (CRF) signalling pathways are involved in the endocrine, behavioural and visceral responses to stress. Recent studies indicate that peripheral CRF-related mechanisms also contribute to stress-induced changes in gut motility and intestinal mucosal function. Peripheral injection of CRF or urocortin inhibits gastric emptying and motility through interaction with CRF 2 receptors and stimulates colonic transit, motility, Fos expression in myenteric neurones and defecation through activation of CRF 1 receptors. With regard to intestinal epithelial cell function, intraperitoneal CRF increases ion secretion and mucosal permeability to macromolecules. The motility and mucosal changes induced by peripheral CRF mimic those induced by acute stress. In addition, CRF receptor antagonists given peripherally prevent acute restraint and water avoidance stress-induced delayed gastric emptying, stimulation of colonic motor function and mucosal permeability. Similarly, early trauma enhanced intestinal mucosal dysfunction to an acute stressor in adult rats and the response is prevented by peripheral injection of CRF antagonist. Chronic psychological stress results in reduced host defence and initiates intestinal inflammation through mast cell-dependent mechanisms. These findings provide convergent evidence that activation of peripheral CRF receptors and mast cells are important mechanisms involved in stress-related alterations of gut physiology.
Neurogastroenterology & Motility, 2012
Background Acute stress-induced hypersensitivity to colorectal distention was shown to depend on corticotropin releasing factor (CRF)-induced mast cell degranulation. At present it remains unclear whether CRF also induces chronic poststress activation of these cells. Accordingly, the objective of this study was to compare pre-and poststress CRF-receptor antagonist treatment protocols for their ability to, respectively, prevent and reverse mast cell dependent visceral hypersensitivity in a rat model of neonatal maternal separation. Methods The visceromotor response to colonic distention was assessed in adult maternally separated and non-handled rats before and at different time points after 1 h of water avoidance (WA). Rats were treated with the mast cell stabilizer doxantrazole and the CRF receptor-antagonist a-helical-CRF (9-41). Western blotting was used to assess mucosal protein levels of the mast cell protease RMCP-2 and the tight junction protein occludin. Key Results In maternally separated, but not in nonhandled rats, WA induced chronic hypersensitivity (up to 30 days) to colorectal distention. Visceral hypersensitivity was prevented, but could not be reversed by administration of a-helical-CRF (9-41). In contrast, however, the mast cell stabilizer doxantrazole reversed visceral hypersensitivity. Compared with vehicle-treated rats, pre-WA a-helical-CRF (9-41) treated animals displayed higher mucosal RMCP-2 and occludin levels. Conclusions & Inferences Water avoidance-stress leads to persistent mast cell dependent visceral hypersensitivity in maternally separated rats, which can be prevented, but not reversed by blockade of peripheral CRF-receptors. We conclude that persistent poststress mast cell activation and subsequent visceral hypersensitivity are not targeted by CRF-receptor antagonists.
Stress-induced visceral hypersensitivity to rectal distension in rats: role of CRF and mast cells
Neurogastroenterology and Motility, 1997
Background: psychological factors have long been implicated in the aetiology of irritable bowel syndrome often associated with abdominal pain. This work was designed to study, in rats, the influence of partial restraint stress on the abdominal cramps induced by rectal distension and to determine the role of corticotropin releasing factor (CRF) and mast cells degranulation in this response. Methods: abdominal contractions were electromyographically recorded. Thirty minutes after stress or intracerebroventricular CRF, rectal distension was performed by inflation of a balloon (0.4±1.2 mL). a-helical CRF 9±41 or doxantrazole were administered centrally (15 min) and intraperitoneally (30 min), respectively, before stress. Histamine release and the number of mast cells were determined in colonic pieces from stressed and control rats. Results: stress and CRF enhanced the number of abdominal cramps evoked by rectal distension without affecting rectal compliance. a-helical CRF 9±41 and doxantrazole antagonized the stress and CRF-induced enhancement of abdominal cramps. Stress increased the colonic histamine content whereas the number of colonic mast cells was unchanged. Conclusions: stress enhances abdominal contractions in response to rectal distension in rats via pathways involving central CRF and intestinal mast cells.
British Journal of Pharmacology, 2004
The characterization of corticotropin releasing factor (CRF) and, more recently, the discovery of additional CRF-related ligands, urocortin 1, urocortin 2 and urocortin 3, the cloning of two distinct CRF receptor subtypes, 1 (CRF 1) and 2 (CRF 2), and the development of selective CRF receptor antagonists provided new insight to unravel the mechanisms of stress. Activation of brain CRF 1 receptor signaling pathways is implicated in stress-related endocrine response and the development of anxiety-like behaviors. 2 Compelling evidence in rodents showed also that both central and peripheral injection of CRF and urocortin 1 mimic acute stress-induced colonic response (stimulation of motility, transit, defecation, mucus and watery secretion, increased ionic permeability and occurrence of diarrhea) in rodents. Central CRF enhances colorectal distention-induced visceral pain in rats. Peripheral CRF reduced pain threshold to colonic distention and increased colonic motility in humans. 3 Nonselective CRF 1 /CRF 2 antagonists and selective CRF 1 antagonists inhibit exogenous (central or peripheral) CRF-and acute stress-induced activation of colonic myenteric neurons, stimulation of colonic motor function and visceral hyperalgesia while selective CRF 2 antagonists have no effect. None of the CRF antagonists influence basal or postprandial colonic function in nonstressed animals. 4 These findings implicate CRF 1 receptors in stress-related stimulation of colonic function and hypersensitivity to colorectal distention. Targeting CRF 1-dependent pathways may have potential benefit against stress or anxiety-/depression-related functional bowel disorders.
The Journal of Physiology, 2007
Neonatal maternal deprivation (NMD) increases gut paracellular permeability (GPP) through mast cells and nerve growth factor (NGF), and modifies corticotrophin-releasing factor (CRF) and corticosterone levels. CRF, corticosterone and mast cells are involved in stress-induced mucosal barrier impairment. Consequently, this study aimed to specify whether corticosteronaemia and colonic expression of both preproCRF and CRF are modified by NMD, and to determine if altered expression may participate in the elevated GPP in connection with NGF and mast cells. Male Wistar rat pups were either separated from postnatal days 2-14, or left undisturbed with their dam. At 12 weeks of age, adult rats were treated with mifepristone (an antagonist of corticoid receptors), α-helical CRF (9-41) (a non-specific CRF receptor antagonist), or SSR-125543 (CRF-R 1 receptor antagonist). We also determined corticosteronaemia and both colonic preproCRF and CRF expression. Then, control rats were treated by CRF, doxantrazole (mast cell stabilizer), BRX-537A (a mast cell activator) and anti-NGF antibody. NMD did not modify colonic CRF level but increased colonic preproCRF expression and corticosteronaemia. Peripheral CRF, via CRF-R 1 receptor, but not corticosterone, was involved in the elevated GPP observed in these rats, through a mast-cell-mediated mechanism, since the increase of GPP induced by exogenous CRF was abolished by doxantrazole. Anti-NGF antibody treatment also reduced the elevated GPP induced by CRF or BRX-537A. CRF acts through CRF-R 1 receptors to stimulate NGF release from mast cells, which participates in the elevated GPP observed in NMD adult rats. This suggests that early traumatic experience induced neuro-endocrine dysfunction, involved in alterations of gut mucosal barrier.
The Journal of physiology, 2004
Recently characterized selective agonists and developed antagonists for the corticotropin releasing factor (CRF) receptors are new tools to investigate stress-related functional changes. The influence of mammalian CRF and related peptides injected intracerebroventricularly (i.c.v.) on gastric and colonic motility, and the CRF receptor subtypes involved and their role in colonic response to stress were studied in conscious mice. The CRF(1)/CRF(2) agonists rat urocortin 1 (rUcn 1) and rat/human CRF (r/h CRF), the preferential CRF(1) agonist ovine CRF (oCRF), and the CRF(2) agonist mouse (m) Ucn 2, injected i.c.v. inhibited gastric emptying and stimulated distal colonic motor function (bead transit and defecation) while oCRF(9-33)OH (devoid of CRF receptor affinity) showed neither effects. mUcn 2 injected peripherally had no colonic effect. The selective CRF(2) antagonist astressin(2)-B (i.c.v.), at a 20 : 1 antagonist: agonist ratio, blocked i.c.v. r/hCRF and rUcn 1 induced inhibition...
2002
Stress may be a contributing factor in intestinal inflammatory disease; however, the underlying mechanisms have not been elucidated. We previously reported that acute stress altered jejunal epithelial physiology. In this study, we examined both physical and psychological stress-induced functional changes in colonic mucosa. Colonic mucosal tissue from rats subjected to either 2 hr of cold-restraint stress or 1 hr of water-avoidance stress demonstrated altered ionic transport as well as significantly elevated baseline conductance (ionic permeability) and flux of horseradish peroxidase (macromolecular permeability). Intraperitoneal pretreatment with the corticotropin-releasing hormone (CRH) antagonist, a helical CRH(9-41), inhibited the stress-induced abnormalities, while exogenous intraperitoneal administration of CRH, to control rats, mimicked the stress responses and in vitro CRH increased the macromolecular permeability. These results suggest that peripheral CRH mediates stress-induced colonic pathophysiology. We speculate that a stress-induced barrier defect may allow uptake of immunogenic substances into the colonic mucosa, initiating or exacerbating intestinal inflammation.
PLoS ONE, 2013
Corticotropin releasing factor receptor 1 (CRF 1) is the key receptor that mediates stress-related body responses. However to date there are no CRF 1 antagonists that have shown clinical efficacy in stress-related diseases. We investigated the inhibitory effects of a new generation, topology 2 selective CRF 1 antagonists, NGD 98-2 and NGD 9002 on exogenous and endogenous CRF-induced stimulation of colonic function and visceral hypersensitivity to colorectal distension (CRD) in conscious rats. CRF 1 antagonists or vehicle were administered orogastrically (og) or subcutaneously (sc) before either intracerebroventricular (icv) or intraperitoneal (ip) injection of CRF (10 mg/kg), exposure to water avoidance stress (WAS, 60 min) or repeated CRD (60 mmHg twice, 10 min on/off at a 30 min interval). Fecal pellet output (FPO), diarrhea and visceromotor responses were monitored. In vehicle (og)-pretreated rats, icv CRF stimulated FPO and induced diarrhea in .50% of rats. NGD 98-2 or NGD 9002 (3, 10 and 30 mg/kg, og) reduced the CRF-induced FPO response with an inhibitory IC 50 of 15.7 and 4.3 mg/kg respectively. At the highest dose, og NGD 98-2 or NGD 9002 blocked icv CRF-induced FPO by 67-87% and decreased WAS-induced-FPO by 23-53%. When administered sc, NGD 98-2 or NGD 9002 (30 mg/kg) inhibited icv and ip CRF-induced-FPO. The antagonists also prevented the development of nociceptive hyper-responsivity to repeated CRD. These data demonstrate that topology 2 CRF 1 antagonists, NGD 98-2 and NGD 9002, administered orally, prevented icv CRF-induced colonic secretomotor stimulation, reduced acute WAS-induced defecation and blocked the induction of visceral sensitization to repeated CRD.
American Journal of Physiology-Gastrointestinal and Liver Physiology, 2009
Corticotropin-releasing factor (CRF) 1 receptor (CRF1) activation in the brain is a core pathway orchestrating the stress response. Anatomical data also support the existence of CRF signaling components within the colon. We investigated the colonic response to intraperitoneal (ip) injection of cortagine, a newly developed selective CRF1 peptide agonist. Colonic motor function and visceral motor response (VMR) were monitored by using a modified miniaturized pressure transducer catheter in adult conscious male Sprague-Dawley rats and C57Bl/6 mice. Colonic permeability was monitored by the Evans blue method and myenteric neurons activation by Fos immunohistochemistry. Compared with vehicle, cortagine (10 μg/kg ip) significantly decreased the distal colonic transit time by 45% without affecting gastric transit, increased distal and transverse colonic contractility by 35.6 and 66.2%, respectively, and induced a 7.1-fold increase in defecation and watery diarrhea in 50% of rats during the...