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1
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Son H, Zhang Y, Shannonhouse J, Ishida H, Gomez R, Kim YS. Mast-cell-specific receptor mediates alcohol-withdrawal-associated headache in male mice. Neuron 2024; 112:113-123.e4. [PMID: 37909038 PMCID: PMC10843090 DOI: 10.1016/j.neuron.2023.09.039] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Revised: 08/13/2023] [Accepted: 09/26/2023] [Indexed: 11/02/2023]
Abstract
Rehabilitation from alcohol addiction or abuse is hampered by withdrawal symptoms including severe headaches, which often lead to rehabilitation failure. There is no appropriate therapeutic option available for alcohol-withdrawal-induced headaches. Here, we show the role of the mast-cell-specific receptor MrgprB2 in the development of alcohol-withdrawal-induced headache. Withdrawing alcohol from alcohol-acclimated mice induces headache behaviors, including facial allodynia, facial pain expressions, and reduced movement, which are symptoms often observed in humans. Those behaviors were absent in MrgprB2-deficient mice during alcohol withdrawal. We observed in vivo spontaneous activation and hypersensitization of trigeminal ganglia (TG) neurons in alcohol-withdrawal WT mice, but not in alcohol-withdrawal MrgprB2-deficient mice. Increased mast cell degranulation by alcohol withdrawal in dura mater was dependent on the presence of MrgprB2. The results indicate that alcohol withdrawal causes headache via MrgprB2 of mast cells in dura mater, suggesting that MrgprB2 is a potential target for treating alcohol-withdrawal-related headaches.
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Affiliation(s)
- Hyeonwi Son
- Department of Oral & Maxillofacial Surgery, School of Dentistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Yan Zhang
- Department of Oral & Maxillofacial Surgery, School of Dentistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - John Shannonhouse
- Department of Oral & Maxillofacial Surgery, School of Dentistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Hirotake Ishida
- Department of Oral & Maxillofacial Surgery, School of Dentistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Ruben Gomez
- Department of Oral & Maxillofacial Surgery, School of Dentistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Yu Shin Kim
- Department of Oral & Maxillofacial Surgery, School of Dentistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA; Programs in Integrated Biomedical Sciences, Translational Sciences, Biomedical Engineering, Radiological Sciences, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
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Szöllősi AG, Oláh A, Lisztes E, Griger Z, Tóth BI. Pruritus: A Sensory Symptom Generated in Cutaneous Immuno-Neuronal Crosstalk. Front Pharmacol 2022; 13:745658. [PMID: 35321329 PMCID: PMC8937025 DOI: 10.3389/fphar.2022.745658] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Accepted: 02/07/2022] [Indexed: 12/21/2022] Open
Abstract
Pruritus or itch generated in the skin is one of the most widespread symptoms associated with various dermatological and systemic (immunological) conditions. Although many details about the molecular mechanisms of the development of both acute and chronic itch were uncovered in the last 2 decades, our understanding is still incomplete and the clinical management of pruritic conditions is one of the biggest challenges in daily dermatological practice. Recent research revealed molecular interactions between pruriceptive sensory neurons and surrounding cutaneous cell types including keratinocytes, as well as resident and transient cells of innate and adaptive immunity. Especially in inflammatory conditions, these cutaneous cells can produce various mediators, which can contribute to the excitation of pruriceptive sensory fibers resulting in itch sensation. There also exists significant communication in the opposite direction: sensory neurons can release mediators that maintain an inflamed, pruritic tissue-environment. In this review, we summarize the current knowledge about the sensory transduction of pruritus detailing the local intercellular interactions that generate itch. We especially emphasize the role of various pruritic mediators in the bidirectional crosstalk between cutaneous non-neuronal cells and sensory fibers. We also list various dermatoses and immunological conditions associated with itch, and discuss the potential immune-neuronal interactions promoting the development of pruritus in the particular diseases. These data may unveil putative new targets for antipruritic pharmacological interventions.
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Affiliation(s)
- Attila Gábor Szöllősi
- Department of Immunology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Attila Oláh
- Department of Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Erika Lisztes
- Department of Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Zoltán Griger
- Division of Clinical Immunology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Balázs István Tóth
- Department of Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
- *Correspondence: Balázs István Tóth,
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3
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Inyang KE, Folger JK, Laumet G. Can FDA-Approved Immunomodulatory Drugs be Repurposed/Repositioned to Alleviate Chronic Pain? J Neuroimmune Pharmacol 2021; 16:531-547. [PMID: 34041656 DOI: 10.1007/s11481-021-10000-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 05/18/2021] [Indexed: 12/11/2022]
Abstract
Pain is among the most widespread chronic health condition confronting society today and our inability to manage chronic pain contributes to the opioid abuse epidemic in America. The immune system is known to contribute to acute and chronic pain, but only limited therapeutic treatments such as non-steroid anti-inflammatory drugs have resulted from this knowledge. The last decade has shed light on neuro-immune interactions mediating the development, maintenance, and resolution of chronic pain. Here, we do not aim to perform a comprehensive review of all immune mechanisms involved in chronic pain, but to briefly review the contribution of the main cytokines and immune cells (macrophages, microglia, mast cells and T cells) to chronic pain. Given the urgent need to address the Pain crisis, we provocatively propose to repurpose/reposition FDA-approved immunomodulatory drugs for their potential to alleviate chronic pain. Repositioning or repurposing offers an attractive way to accelerate the arrival of new analgesics.
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Affiliation(s)
| | - Joseph K Folger
- Department of Physiology, Michigan State University, East Lansing, MI, USA
| | - Geoffroy Laumet
- Department of Physiology, Michigan State University, East Lansing, MI, USA.
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della Rocca G, Gamba D. Chronic Pain in Dogs and Cats: Is There Place for Dietary Intervention with Micro-Palmitoylethanolamide? Animals (Basel) 2021; 11:952. [PMID: 33805489 PMCID: PMC8065429 DOI: 10.3390/ani11040952] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 03/23/2021] [Accepted: 03/23/2021] [Indexed: 12/17/2022] Open
Abstract
The management of chronic pain is an integral challenge of small animal veterinary practitioners. Multiple pharmacological agents are usually employed to treat maladaptive pain including opiates, non-steroidal anti-inflammatory drugs, anticonvulsants, antidepressants, and others. In order to limit adverse effects and tolerance development, they are often combined with non-pharmacologic measures such as acupuncture and dietary interventions. Accumulating evidence suggests that non-neuronal cells such as mast cells and microglia play active roles in the pathogenesis of maladaptive pain. Accordingly, these cells are currently viewed as potential new targets for managing chronic pain. Palmitoylethanolamide is an endocannabinoid-like compound found in several food sources and considered a body's own analgesic. The receptor-dependent control of non-neuronal cells mediates the pain-relieving effect of palmitoylethanolamide. Accumulating evidence shows the anti-hyperalgesic effect of supplemented palmitoylethanolamide, especially in the micronized and co-micronized formulations (i.e., micro-palmitoylethanolamide), which allow for higher bioavailability. In the present paper, the role of non-neuronal cells in pain signaling is discussed and a large number of studies on the effect of palmitoylethanolamide in inflammatory and neuropathic chronic pain are reviewed. Overall, available evidence suggests that there is place for micro-palmitoylethanolamide in the dietary management of chronic pain in dogs and cats.
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Affiliation(s)
- Giorgia della Rocca
- Department of Veterinary Medicine, Centro di Ricerca sul Dolore Animale (CeRiDA), Università degli Studi di Perugia, 06123 Perugia, Italy
| | - Davide Gamba
- Operational Unit of Anesthesia, Centro Veterinario Gregorio VII, 00165 Roma, Italy;
- Freelance, DG Vet Pain Therapy, 24124 Bergamo, Italy
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5
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Abstract
Mast cells are innate immune cells that intersect with the adaptive immunity and play a crucial role in the initiation of allergic reactions and the host defense against certain parasites and venoms. When activated in an allergen- and immunoglobulin E (IgE)-dependent manner, these cells secrete a large variety of allergenic mediators that are pre-stored in secretory granules or
de novo–synthesized. Traditionally, studies have predominantly focused on understanding this mechanism of mast cell activation and regulation. Along this line of study, recent studies have shed light on what structural features are required for allergens and how IgE, particularly anaphylactic IgE, is produced. However, the last few years have seen a flurry of new studies on IgE-independent mast cell activation, particularly via Mrgprb2 (mouse) and MRGPRX2 (human). These studies have greatly advanced our understanding of how mast cells exert non-histaminergic itch, pain, and drug-induced pseudoallergy by interacting with sensory neurons. Recent studies have also characterized mast cell activation and regulation by interleukin-33 (IL-33) and other cytokines and by non-coding RNAs. These newly identified mechanisms for mast cell activation and regulation will further stimulate the allergy/immunology community to develop novel therapeutic strategies for treatment of allergic and non-allergic diseases.
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Affiliation(s)
- Hwan Soo Kim
- Division of Cell Biology, La Jolla Institute for Immunology, La Jolla, California, 92037, USA.,Department of Pediatrics, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Yu Kawakami
- Division of Cell Biology, La Jolla Institute for Immunology, La Jolla, California, 92037, USA
| | - Kazumi Kasakura
- Division of Cell Biology, La Jolla Institute for Immunology, La Jolla, California, 92037, USA
| | - Toshiaki Kawakami
- Division of Cell Biology, La Jolla Institute for Immunology, La Jolla, California, 92037, USA.,Department of Dermatlogy, University of California San Diego, School of Medicine, La Jolla, CA, 92093, USA
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6
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Meixiong J, Basso L, Dong X, Gaudenzio N. Nociceptor-Mast Cell Sensory Clusters as Regulators of Skin Homeostasis. Trends Neurosci 2020; 43:130-132. [PMID: 32014258 DOI: 10.1016/j.tins.2020.01.001] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Accepted: 01/06/2020] [Indexed: 01/17/2023]
Abstract
Recent studies revealed the existence of unique functional links between mast cells and nociceptors in the skin. Here, we propose that mast cells and nociceptors form a single regulatory unit in both physiology and disease. In this model, MrgprB2/X2 signaling is a primary mechanism by which mast cells functionally interact with nociceptors to form specialized neuroimmune clusters that regulate pain, inflammation, and itch.
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Affiliation(s)
- James Meixiong
- The Solomon H. Snyder Department of Neuroscience, Center for Sensory Biology Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA
| | - Lilian Basso
- Unité de Différenciation Epithéliale et Autoimmunité Rhumatoïde (UDEAR), UMR 1056, INSERM, Université de Toulouse, 31059 Toulouse, France
| | - Xinzhong Dong
- The Solomon H. Snyder Department of Neuroscience, Center for Sensory Biology Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA; Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
| | - Nicolas Gaudenzio
- Unité de Différenciation Epithéliale et Autoimmunité Rhumatoïde (UDEAR), UMR 1056, INSERM, Université de Toulouse, 31059 Toulouse, France.
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7
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Ogasawara H, Furuno M, Edamura K, Noguchi M. Novel MRGPRX2 antagonists inhibit IgE‐independent activation of human umbilical cord blood‐derived mast cells. J Leukoc Biol 2019; 106:1069-1077. [DOI: 10.1002/jlb.2ab1018-405r] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Revised: 06/11/2019] [Accepted: 07/01/2019] [Indexed: 12/12/2022] Open
Affiliation(s)
- Hiroyuki Ogasawara
- Pharmaceutical Frontier Research LaboratoriesCentral Pharmaceutical Research InstituteJapan Tobacco Inc. Yokohama Kanagawa Japan
| | - Masahiro Furuno
- Pharmaceutical Frontier Research LaboratoriesCentral Pharmaceutical Research InstituteJapan Tobacco Inc. Yokohama Kanagawa Japan
| | - Koji Edamura
- Pharmaceutical Frontier Research LaboratoriesCentral Pharmaceutical Research InstituteJapan Tobacco Inc. Yokohama Kanagawa Japan
| | - Masato Noguchi
- Pharmaceutical Frontier Research LaboratoriesCentral Pharmaceutical Research InstituteJapan Tobacco Inc. Yokohama Kanagawa Japan
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8
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Flores JA, Ramírez-Ponce MP, Montes MÁ, Balseiro-Gómez S, Acosta J, Álvarez de Toledo G, Alés E. Proteoglycans involved in bidirectional communication between mast cells and hippocampal neurons. J Neuroinflammation 2019; 16:107. [PMID: 31109355 PMCID: PMC6528191 DOI: 10.1186/s12974-019-1504-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Accepted: 05/08/2019] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Mast cells (MCs) in the brain can respond to environmental cues and relay signals to neurons that may directly influence neuronal electrical activity, calcium signaling, and neurotransmission. MCs also express receptors for neurotransmitters and consequently can be activated by them. Here, we developed a coculture model of peritoneal MCs, incubated together with dissociated hippocampal neurons for the study of cellular mechanisms involved in the mast cell-neuron interactions. METHODS Calcium imaging was used to simultaneously record changes in intracellular calcium [Ca2+]i in neurons and MCs. To provide insight into the contribution of MCs on neurotransmitter release in rat hippocampal neurons, we used analysis of FM dye release, evoked by a cocktail of mediators from MCs stimulated by heat. RESULTS Bidirectional communication is set up between MCs and hippocampal neurons. Neuronal depolarization caused intracellular calcium [Ca2+]i oscillations in MCs that produced a quick response in neurons. Furthermore, activation of MCs with antigen or the secretagogue compound 48/80 also resulted in a neuronal [Ca2+]i response. Moreover, local application onto neurons of the MC mediator cocktail elicited Ca2+ transients and a synaptic release associated with FM dye destaining. Neuronal response was partially blocked by D-APV, a N-methyl-D-aspartate receptor (NMDAR) antagonist, and was inhibited when the cocktail was pre-digested with chondroitinase ABC, which induces enzymatic removal of proteoglycans of chondroitin sulfate (CS). CONCLUSIONS MC-hippocampal neuron interaction affects neuronal [Ca2+]i and exocytosis signaling through a NMDAR-dependent mechanism.
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Affiliation(s)
- Juan Antonio Flores
- Dpto. de Fisiología Médica y Biofísica, Facultad de Medicina, Universidad de Sevilla, Av. Sánchez Pizjuán 4, 41009 Sevilla, Spain
| | - María Pilar Ramírez-Ponce
- Dpto. de Fisiología Médica y Biofísica, Facultad de Medicina, Universidad de Sevilla, Av. Sánchez Pizjuán 4, 41009 Sevilla, Spain
| | - María Ángeles Montes
- Dpto. de Fisiología Médica y Biofísica, Facultad de Medicina, Universidad de Sevilla, Av. Sánchez Pizjuán 4, 41009 Sevilla, Spain
| | - Santiago Balseiro-Gómez
- Dpto. de Fisiología Médica y Biofísica, Facultad de Medicina, Universidad de Sevilla, Av. Sánchez Pizjuán 4, 41009 Sevilla, Spain
- Present Address: Department of Neuroscience, Yale School of Medicine, 295 Congress Avenue, New Haven, CT 06510 USA
| | - Jorge Acosta
- Dpto. de Fisiología Médica y Biofísica, Facultad de Medicina, Universidad de Sevilla, Av. Sánchez Pizjuán 4, 41009 Sevilla, Spain
| | - Guillermo Álvarez de Toledo
- Dpto. de Fisiología Médica y Biofísica, Facultad de Medicina, Universidad de Sevilla, Av. Sánchez Pizjuán 4, 41009 Sevilla, Spain
| | - Eva Alés
- Dpto. de Fisiología Médica y Biofísica, Facultad de Medicina, Universidad de Sevilla, Av. Sánchez Pizjuán 4, 41009 Sevilla, Spain
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Phenotyping patients with chronic cough: Evaluating the ability to predict the response to anti-inflammatory therapy. Ann Allergy Asthma Immunol 2018; 120:285-291. [PMID: 29508715 DOI: 10.1016/j.anai.2017.12.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2017] [Revised: 11/30/2017] [Accepted: 12/11/2017] [Indexed: 11/23/2022]
Abstract
BACKGROUND Whether the fraction of exhaled nitric oxide (FeNO) measurement can predict the response to anti-inflammatory treatment in chronic cough is unknown. OBJECTIVE To explore whether the effectiveness of treatment with 10 mg of montelukast or 20 mg of prednisolone in patients with chronic cough is predicted by FeNO level. METHODS In this randomized, open-label, controlled pilot study conducted in the Clinical Trial Unit in Castle Hospital in the United Kingdom, 50 nonsmoking patients with a cough that lasted more than 8 weeks were sequentially enrolled in the study. Thirty patients with high FeNO levels (≥30 ppb) were randomized in a 1:1 ratio to receive 10 mg of montelukast or 20 mg of prednisolone for 2 weeks followed by 10 mg of montelukast for 2 weeks. Twenty patients with a low FeNO level (≤20 ppb) received 10 mg of montelukast. The primary objective was to determine the effectiveness of treatment on 24-hour cough counts. RESULTS The 24-hour cough counts decreased in both groups by approximately 50% (P < .005), indicating that FeNO did not predict treatment response. However, it was a good marker for eosinophilic inflammation with a high degree of correlation with blood and sputum eosinophilia (P < .001). CONCLUSION These results suggest that prior investigation may not predict response to anti-inflammatory treatment, which may be consequent on localized leukotriene-mediated inflammation. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02479074.
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Verma AK, Manohar M, Upparahalli Venkateshaiah S, Mishra A. Neuroendocrine cells derived chemokine vasoactive intestinal polypeptide (VIP) in allergic diseases. Cytokine Growth Factor Rev 2017; 38:37-48. [PMID: 28964637 DOI: 10.1016/j.cytogfr.2017.09.002] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2017] [Revised: 09/21/2017] [Accepted: 09/22/2017] [Indexed: 12/20/2022]
Abstract
Worldwide increase incidences of allergic diseases have heightened the interest of clinicians and researchers to understand the role of neuroendocrine cells in the recruitment and activation of inflammatory cells. Several pieces of evidence revealed the association of neuropeptides in the pathogenesis of allergic diseases. Importantly, one such peptide that is secreted by neuronal cells and immune cells exerts a wide spectrum of immunological functions as cytokine/chemokine is termed as Vasoactive Intestinal Peptide (VIP). VIP mediates immunological function through interaction with specific receptors namely VPAC-1, VPAC-2, CRTH2 and PAC1 that are expressed on several immune cells such as eosinophils, mast cells, neutrophils, and lymphocytes; therefore, provide the basis for the action of VIP on the immune system. Additionally, VIP mediated action varies according to target organ depending upon the presence of specific VIP associated receptor, involved immune cells and the microenvironment of the organ. Herein, we present an integrative review of the current understanding on the role of VIP and associated receptors in allergic diseases, the presence of VIP receptors on various immune cells with particular emphasis on the role of VIP in the pathogenesis of allergic diseases such as asthma, allergic rhinitis, and atopic dermatitis. Being crucial signal molecule of the neuroendocrine-immune network, the development of stable VIP analogue and/or antagonist may provide the future therapeutic drug alternative for the better treatment of these allergic diseases. Taken together, our current review summarizes the current understandings of VIP biology and further explore the significance of neuroendocrine cells derived VIP in the recruitment of inflammatory cells in allergic diseases that may be helpful to the investigators for planning the experiments and accordingly predicting new therapeutic strategies for combating allergic diseases. Summarized graphical abstract will help the readers to understand the significance of VIP in allergic diseases.
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Affiliation(s)
- Alok K Verma
- Department of Medicine, Section of Pulmonary Diseases, Tulane Eosinophilic Disorders Center, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Murli Manohar
- Department of Medicine, Section of Pulmonary Diseases, Tulane Eosinophilic Disorders Center, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Sathisha Upparahalli Venkateshaiah
- Department of Medicine, Section of Pulmonary Diseases, Tulane Eosinophilic Disorders Center, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Anil Mishra
- Department of Medicine, Section of Pulmonary Diseases, Tulane Eosinophilic Disorders Center, Tulane University School of Medicine, New Orleans, LA 70112, USA.
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11
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Allergic airway inflammation induces migration of mast cell populations into the mouse airway. Cell Tissue Res 2017; 369:331-340. [PMID: 28343320 DOI: 10.1007/s00441-017-2597-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2016] [Accepted: 02/23/2017] [Indexed: 12/21/2022]
Abstract
Mast cells (MCs) and airway nerves play an important role in allergic asthma. However, little is known about the MCs and their interaction with airway nerves during allergic airway inflammation. This study aims to investigate the distribution and proliferation of MC populations in different lung compartments, along with the association of mast cells with nerve endings, using a house dust mite (HDM) model for allergic airway inflammation. BALB/c mice were exposed to HDM extract intranasally (25 μg/50 μl) for 5 consecutive days a week over 7 weeks. Immunofluorescence and Edu stains were used to examine the colocalisation of MCs and nerves and the proliferation of MCs, respectively. HDM treatment caused an increased migration of MCs into bronchi, alveolar parenchyma and airway vessels. The proportions of tryptase-chymase expressing MC (MCTC) increased significantly in the bronchi and the alveolar parenchyma but not in the vascular tissues, by allergic airway inflammation. The association of MCs with nerves was found only in the bronchi and there were no changes in comparison of controls to HDM-treated animals. The present study shows a strong migration of tryptase expressing MC (MCT) and MCTC into the bronchi and the alveolar parenchyma, as well as of MCT in the vascular compartment under HDM treatment. This supports the hypothesis that these mast cell populations may contribute to allergic airway inflammation.
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12
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In silico design of novel probes for the atypical opioid receptor MRGPRX2. Nat Chem Biol 2017; 13:529-536. [PMID: 28288109 PMCID: PMC5391270 DOI: 10.1038/nchembio.2334] [Citation(s) in RCA: 221] [Impact Index Per Article: 27.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2016] [Accepted: 12/22/2016] [Indexed: 12/19/2022]
Abstract
The primate-exclusive MRGPRX2 G protein-coupled receptor (GPCR) has been suggested to modulate pain and itch. Despite putative peptide and small molecule MRGPRX2 agonists, selective nanomolar potency probes have not yet been reported. To identify a MRGPRX2 probe, we first screened 5,695 small molecules and found many opioid compounds activated MRGPRX2, including (−)- and (+)-morphine, hydrocodone, sinomenine, dextromethorphan and the prodynorphin-derived peptides, dynorphin A, dynorphin B, and α- and β-neoendorphin. We used these to select for mutagenesis-validated homology models and docked almost 4 million small molecules. From this docking, we predicted ZINC-3573, which represents a potent MRGPRX2-selective agonist, showing little activity against 315 other GPCRs and 97 representative kinases, and an essentially inactive enantiomer. ZINC-3573 activates endogenous MRGPRX2 in a human mast cell line inducing degranulation and calcium release. MRGPRX2 is a unique atypical opioid-like receptor important for modulating mast cell degranulation, which can now be specifically modulated with ZINC-3573.
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13
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He W, Wang XY, Shi H, Bai WZ, Cheng B, Su YS, Yu XC, Jing XH, Zhu B. Cutaneous neurogenic inflammation in the sensitized acupoints induced by gastric mucosal injury in rats. Altern Ther Health Med 2017; 17:141. [PMID: 28270193 PMCID: PMC5341424 DOI: 10.1186/s12906-017-1580-z] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2016] [Accepted: 01/12/2017] [Indexed: 11/10/2022]
Abstract
BACKGROUND In acupuncture practice, the most important step is to confirm the location of a sensitized acupoint which reflects a diagnosis and can be stimulated with a specialized needle to treat the disease. Abnormal symptoms such as hyperalgesia or allodynia at the sensitized acupoints in patients with visceral disorders are considered to be in relation with referred pain and neurogenic inflammation. Yet, limited study has investigated the cutaneous neurochemical changes of the sensitized acuponits. METHODS The resent study developed an animal model of gastric mucosal injury (GMI) by HCl administered into the stomach of the rats. Evans Blue (EB) dye was applied by injection of tail vein after mucosal damage to observe the neurogenic plasma extravasation dots in the skin of the rats. The EB dots extravagated in the skin were compared with locations of acupoints. Immnohistochemistry analysis was used to detect the expression of calcitonin gene-related peptide (CGRP)- or substance P (SP)-labeled nerve fibers, histamine (HA)-, serotonin (5-HT)-, and tryptase-labeled cells in EB dots. Images were recorded and analyzed by Confocal imaging system and Olympus Image Processing Software. RESULTS The results showed that GMI resulted in neurogenic plasma extravasation in the skin of the acupoints over the back and abdomen, which mostly occurred in the T9-11 dermatomere. The EB extravasation dots appeared after GMI and disappeared gradually during the natural self-recovery of the gastric mucosa. More SP and CGRP positive nerve fibers were distributed in EB dots than that in regions beside EB dots and in the control, mostly distributed in the nerve fibers around both the vessels and root of hair follicle. Mast cells also aggregated and degranulated to release algogenic substances of 5-HT and HA around the vessels in areas of the EB dots. CONCLUSIONS Our results indicates that the mechanism of EB extravasation in the skin of the acupoints induced by GMI are closely related to neurogenic inflammation, and that the high expression of local allergic substances and nociceptive neuropeptides in the local skin including SP, CGRP, HA, 5-HT, and mast cell tryptase may be the underlying mechanism of the acupoint sensitization.
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Abstract
Mast cells (MCs) play a central role in tissue homoeostasis, sensing the local environment through numerous innate cell surface receptors. This enables them to respond rapidly to perceived tissue insults with a view to initiating a co-ordinated programme of inflammation and repair. However, when the tissue insult is chronic, the ongoing release of multiple pro-inflammatory mediators, proteases, cytokines and chemokines leads to tissue damage and remodelling. In asthma, there is strong evidence of ongoing MC activation, and their mediators and cell-cell signals are capable of regulating many facets of asthma pathophysiology. This article reviews the evidence behind this.
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Affiliation(s)
- P Bradding
- Department of Infection, Immunity and Inflammation, Institute for Lung Health, University of Leicester, Leicester, UK
| | - G Arthur
- Department of Infection, Immunity and Inflammation, Institute for Lung Health, University of Leicester, Leicester, UK
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15
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Subramanian H, Gupta K, Ali H. Roles of Mas-related G protein-coupled receptor X2 on mast cell-mediated host defense, pseudoallergic drug reactions, and chronic inflammatory diseases. J Allergy Clin Immunol 2016; 138:700-710. [PMID: 27448446 DOI: 10.1016/j.jaci.2016.04.051] [Citation(s) in RCA: 303] [Impact Index Per Article: 33.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2016] [Revised: 03/21/2016] [Accepted: 04/06/2016] [Indexed: 12/11/2022]
Abstract
Mast cells (MCs), which are granulated tissue-resident cells of hematopoietic lineage, contribute to vascular homeostasis, innate/adaptive immunity, and wound healing. However, MCs are best known for their roles in allergic and inflammatory diseases, such as anaphylaxis, food allergy, rhinitis, itch, urticaria, atopic dermatitis, and asthma. In addition to the high-affinity IgE receptor (FcεRI), MCs express numerous G protein-coupled receptors (GPCRs), which are the largest group of membrane receptor proteins and the most common targets of drug therapy. Antimicrobial host defense peptides, neuropeptides, major basic protein, eosinophil peroxidase, and many US Food and Drug Administration-approved peptidergic drugs activate human MCs through a novel GPCR known as Mas-related G protein-coupled receptor X2 (MRGPRX2; formerly known as MrgX2). Unique features of MRGPRX2 that distinguish it from other GPCRs include their presence both on the plasma membrane and intracellular sites and their selective expression in MCs. In this article we review the possible roles of MRGPRX2 on host defense, drug-induced anaphylactoid reactions, neurogenic inflammation, pain, itch, and chronic inflammatory diseases, such as urticaria and asthma. We propose that host defense peptides that kill microbes directly and activate MCs through MRGPRX2 could serve as novel GPCR targets to modulate host defense against microbial infection. Furthermore, mAbs or small-molecule inhibitors of MRGPRX2 could be developed for the treatment of MC-dependent allergic and inflammatory disorders.
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Affiliation(s)
- Hariharan Subramanian
- Department of Pathology, University of Pennsylvania School of Dental Medicine, Philadelphia, Pa
| | - Kshitij Gupta
- Department of Pathology, University of Pennsylvania School of Dental Medicine, Philadelphia, Pa
| | - Hydar Ali
- Department of Pathology, University of Pennsylvania School of Dental Medicine, Philadelphia, Pa.
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In vivo Monitoring of Serotonin by Nanomaterial Functionalized Acupuncture Needle. Sci Rep 2016; 6:28018. [PMID: 27301303 PMCID: PMC4908407 DOI: 10.1038/srep28018] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2016] [Accepted: 05/27/2016] [Indexed: 12/17/2022] Open
Abstract
Acupuncture treatment is amazing but controversial. Up to now, the mechanism of treating diseases by acupuncture and moxibustion is still unclear, especially the occurrence of the molecular events in local acupoints. Herein, we report an extremely stable microsensor by modifying carbon nanotube (CNT) to the tip surface of acupuncture needle and applying this CNT-modified acupuncture needle for real time monitoring of serotonin (5-HT) in vivo. To stabilize CNT modification on the needle tip surface, poly(3,4-ethylenedioxythiophene)(PEDOT) was employed as glue water to stick CNT on the needle. The detection limit of the CNT-modified needle was found to be approximately 50 nM and 78 nM in the PBS and the cell medium, respectively. In addition, the needle showed good selectivity to some inflammatory mediators and some electroactive molecules. For the first time, the CNT-modified needle could be directly probed into rat body for real time monitoring of 5-HT in vivo, showing a great potential for better understanding the mechanism of acupuncture treatment.
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17
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18
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Wu ML, Xu DS, Bai WZ, Cui JJ, Shu HM, He W, Wang XY, Shi H, Su YS, Hu L, Zhu B, Jing XH. Local cutaneous nerve terminal and mast cell responses to manual acupuncture in acupoint LI4 area of the rats. J Chem Neuroanat 2015; 68:14-21. [PMID: 26148746 DOI: 10.1016/j.jchemneu.2015.06.002] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2015] [Revised: 06/08/2015] [Accepted: 06/22/2015] [Indexed: 10/23/2022]
Abstract
Previous studies have shown that the effects of manual acupuncture (MA) are contributed by collagen fibers and mast cells in local acupoints, at which acupuncture stimulation causes various afferent fiber groups to be excited. However what happens in local nerve fibers and mast cells after MA remains unclear. The aim of this study was to examine the response of cutaneous nerve fibers and mast cells to MA stimulation in acupoint Hegu (LI4). The contralateral LI4 of the same rat was used as a non-stimulated control. Immnohistochemistry analysis were carried out to observe the expression of histamine (HA), serotonin (5-HT) and nociceptive neuropeptides, calcitonin gene-related peptide (CGRP) and substance P (SP), in the LI4 area. Mast cells were labeled with anti-mast cell tryptase antibody and simultaneously with HA or 5-HT primary antibodies to observe their co-expression. Our results showed that SP and CGRP were expressed more highly on the cutaneous nerve fibers of LI4 after MA stimulation than that of the control. Mast cells aggregated in close proximity to the blood vessels in intra-epidermis and dermis and some of them with degranulation in the lower dermis and subcutaneous tissue of LI4. Both mast cells and their granules appeared with HA (+) and 5-HT (+) expression at stimulated L14 sites, while a few intact mast cells with a little expression of 5-HT and HA were distributed in areas of non-stimulated L14. The results indicated that local cutaneous nerve terminals and mast cells responded to MA with higher expression of SP and CGRP in nerve fibers, as well as with aggregation and degranulation of mast cells with HA and 5-HT granules at acupoint LI4. These neuroactive substances may convey signals to certain pathways that contribute to the effects of acupuncture.
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Affiliation(s)
- Mei-Ling Wu
- Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing 100700, China.
| | - Dong-Sheng Xu
- Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing 100700, China.
| | - Wan-Zhu Bai
- Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing 100700, China.
| | - Jing-Jing Cui
- Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing 100700, China.
| | - Hong-Ming Shu
- Shandong University of Traditional Chinese Medicine, Jinan 250014, China.
| | - Wei He
- Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing 100700, China.
| | - Xiao-Yu Wang
- Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing 100700, China.
| | - Hong Shi
- Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing 100700, China.
| | - Yang-Shuai Su
- Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing 100700, China.
| | - Ling Hu
- Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing 100700, China.
| | - Bing Zhu
- Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing 100700, China; Shandong University of Traditional Chinese Medicine, Jinan 250014, China.
| | - Xiang-Hong Jing
- Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing 100700, China.
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19
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Burnstock G, Boeynaems JM. Purinergic signalling and immune cells. Purinergic Signal 2014; 10:529-64. [PMID: 25352330 PMCID: PMC4272370 DOI: 10.1007/s11302-014-9427-2] [Citation(s) in RCA: 236] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2013] [Accepted: 09/12/2013] [Indexed: 11/28/2022] Open
Abstract
This review article provides a historical perspective on the role of purinergic signalling in the regulation of various subsets of immune cells from early discoveries to current understanding. It is now recognised that adenosine 5'-triphosphate (ATP) and other nucleotides are released from cells following stress or injury. They can act on virtually all subsets of immune cells through a spectrum of P2X ligand-gated ion channels and G protein-coupled P2Y receptors. Furthermore, ATP is rapidly degraded into adenosine by ectonucleotidases such as CD39 and CD73, and adenosine exerts additional regulatory effects through its own receptors. The resulting effect ranges from stimulation to tolerance depending on the amount and time courses of nucleotides released, and the balance between ATP and adenosine. This review identifies the various receptors involved in the different subsets of immune cells and their effects on the function of these cells.
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Affiliation(s)
- Geoffrey Burnstock
- Autonomic Neuroscience Centre, University College Medical School, Rowland Hill Street, London, NW3 2PF, UK,
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20
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Förster A, Preussner LM, Seeger JM, Rabenhorst A, Kashkar H, Mrowietz U, Hartmann K. Dimethylfumarate induces apoptosis in human mast cells. Exp Dermatol 2014; 22:719-24. [PMID: 24112621 DOI: 10.1111/exd.12247] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/17/2013] [Indexed: 12/30/2022]
Abstract
Mast cells modulate autoimmune diseases such as psoriasis and multiple sclerosis. Fumaric acid esters (FAEs) are widely used for the treatment of psoriasis, and dimethylfumarate (DMF) has recently been approved for multiple sclerosis. In this study, we analysed the cytotoxic effect of FAEs on human mast cells. Specifically, cell death was analysed in the human mast cell line HMC-1 and in primary cord blood-derived mast cells (CBMCs) after incubation with fumaric acid (FA), monomethylfumarate (MMF), DMF and calcium bis(monomethylfumarate) (Ca-MF). Our data show that only DMF potently induces apoptotic cell death in HMC-1 cells and CBMCs. DMF-mediated apoptosis was associated with increased expression of Bax and Bak and activation of caspase-9 and caspase-6. Interestingly, DMF also enhanced the sensitivity of CBMCs towards TRAIL- and dexamethasone-induced apoptosis. These findings demonstrate for the first time that DMF induces apoptosis of human mast cells, primarily via the mitochondrial apoptotic pathway. Our study contributes to the understanding of the beneficial effects of FAEs in autoimmune diseases and provides a rationale for exploiting FAEs for other diseases associated with mast cells.
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Affiliation(s)
- Anja Förster
- Department of Dermatology, University of Cologne, Cologne, Germany
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21
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Oh MH, Oh SY, Lu J, Lou H, Myers AC, Zhu Z, Zheng T. TRPA1-dependent pruritus in IL-13-induced chronic atopic dermatitis. THE JOURNAL OF IMMUNOLOGY 2013; 191:5371-82. [PMID: 24140646 DOI: 10.4049/jimmunol.1300300] [Citation(s) in RCA: 153] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Chronic debilitating pruritus is a cardinal feature of atopic dermatitis (AD). Little is known about the underlying mechanisms. Antihistamines lack efficacy in treating itch in AD, suggesting the existence of histamine-independent itch pathways in AD. Transient receptor potential ankyrin 1 (TRPA1) is essential in the signaling pathways that promote histamine-independent itch. In this study, we tested the hypothesis that TRPA1-dependent neural pathways play a key role in chronic itch in AD using an IL-13-transgenic mouse model of AD. In these mice, IL-13 causes chronic AD characterized by intensive chronic itch associated with markedly enhanced growth of dermal neuropeptide-secreting afferent nerve fibers and enhanced expression of TRPA1 in dermal sensory nerve fibers, their dorsal root ganglia, and mast cells. Inhibition of TRPA1 with a specific antagonist in these mice selectively attenuated itch-evoked scratching. Genetic deletion of mast cells in these mice led to significantly diminished itch-scratching behaviors and reduced TRPA1 expression in dermal neuropeptide containing afferents in the AD skin. Interestingly, IL-13 strongly stimulates TRPA1 expression, which is functional in calcium mobilization in mast cells. In accordance with these observations in the AD mice, TRPA1 expression was highly enhanced in the dermal afferent nerves, mast cells, and the epidermis in the lesional skin biopsies from patients with AD, but not in the skin from healthy subjects. These studies demonstrate a novel neural mechanism underlying chronic itch in AD and highlight the complex interactions among TRPA1(+) dermal afferent nerves and TRPA1(+) mast cells in a Th2-dominated inflammatory environment.
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Affiliation(s)
- Min-Hee Oh
- Division of Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, MD 21224
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22
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Abstract
Mast cells are well known as principle effector cells of type I hypersensitivity responses. Beyond this role in allergic disease, these cells are now appreciated as playing an important role in many inflammatory conditions. This review summarizes the support for mast cell involvement in resisting bacterial infection, exacerbating autoimmunity and atherosclerosis, and promoting cancer progression. A commonality in these conditions is the ability of mast cells to elicit migration of many cell types, often through the production of inflammatory cytokines such as tumor necrosis factor. However, recent data also demonstrates that mast cells can suppress the immune response through interleukin-10 production. The data encourage those working in this field to expand their view of how mast cells contribute to immune homeostasis.
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23
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Rudich N, Ravid K, Sagi-Eisenberg R. Mast cell adenosine receptors function: a focus on the a3 adenosine receptor and inflammation. Front Immunol 2012; 3:134. [PMID: 22675325 PMCID: PMC3366457 DOI: 10.3389/fimmu.2012.00134] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2012] [Accepted: 05/09/2012] [Indexed: 12/13/2022] Open
Abstract
Adenosine is a metabolite, which has long been implicated in a variety of inflammatory processes. Inhaled adenosine provokes bronchoconstriction in asthmatics or chronic obstructive pulmonary disease patients, but not in non-asthmatics. This hyper responsiveness to adenosine appears to be mediated by mast cell activation. These observations have marked the receptor that mediates the bronchoconstrictor effect of adenosine on mast cells (MCs), as an attractive drug candidate. Four subtypes (A1, A2a, A2b, and A3) of adenosine receptors have been cloned and shown to display distinct tissue distributions and functions. Animal models have firmly established the ultimate role of the A3 adenosine receptor (A3R) in mediating hyper responsiveness to adenosine in MCs, although the influence of the A2b adenosine receptor was confirmed as well. In contrast, studies of the A3R in humans have been controversial. In this review, we summarize data on the role of different adenosine receptors in mast cell regulation of inflammation and pathology, with a focus on the common and distinct functions of the A3R in rodent and human MCs. The relevance of mouse studies to the human is discussed.
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Affiliation(s)
- Noam Rudich
- Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University Tel Aviv, Israel
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24
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Mast cell–nerve axis with a focus on the human gut. Biochim Biophys Acta Mol Basis Dis 2012; 1822:85-92. [DOI: 10.1016/j.bbadis.2011.06.004] [Citation(s) in RCA: 110] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2011] [Revised: 06/07/2011] [Accepted: 06/10/2011] [Indexed: 02/07/2023]
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25
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De Winter BY, van den Wijngaard RM, de Jonge WJ. Intestinal mast cells in gut inflammation and motility disturbances. BIOCHIMICA ET BIOPHYSICA ACTA 2012; 1822:66-73. [PMID: 21497195 DOI: 10.1016/j.bbadis.2011.03.016] [Citation(s) in RCA: 103] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/25/2011] [Revised: 03/20/2011] [Accepted: 03/25/2011] [Indexed: 12/12/2022]
Abstract
Mast cells may be regarded as prototypes of innate immune cells that can be controlled by neuronal mediators. Their activation has been implicated in many types of neuro-inflammatory responses, and related disturbances of gut motility, via direct or indirect mechanisms that involve several mechanisms relevant to disease pathogenesis such as changes in epithelial barrier function or activation of adaptive or innate immune responses. Here we review the evidence for the involvement of mast cells in the inflammation of the bowel wall caused by bowel manipulation that leads to motility disturbances such as postoperative gastroparesis and ileus. Also in IBD there is substantial evidence for the involvement of mast cells and a mast cell-mediated neuroimmune interaction showing an increased number and an increased degranulation of mast cells. We discuss the potential of mast cell inhibition as a bona fide drug target to relief postoperative ileus. Further research on mast cell-related therapy either by stabilizing the mast cells or by blocking specific mast cell mediators as adjunctive therapy in IBD is encouraged, bearing in mind that several drugs currently used in the treatment of IBD possess properties affecting mast cell activities. This article is part of a Special Issue entitled: Mast cells in inflammation.
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Affiliation(s)
- Benedicte Y De Winter
- Laboratory of Experimental Medicine and Pediatrics, Department of Gastroenterology, University of Antwerp, Antwerp, Belgium
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26
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Liezmann C, Klapp B, Peters EM. Stress, atopy and allergy: A re-evaluation from a psychoneuroimmunologic persepective. DERMATO-ENDOCRINOLOGY 2011; 3:37-40. [PMID: 21519408 DOI: 10.4161/derm.3.1.14618] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/02/2010] [Revised: 12/10/2010] [Accepted: 12/21/2010] [Indexed: 01/08/2023]
Abstract
Since the early days of psychosomatic thinking, atopic disease was considered exemplary. In the 70s and 80s numerous reports stated increased anxiety, depression or ill stresscoping in atopics in correlation with enhanced disease activity. Employed patient groups however were small and diverse and controls rare. Therefore, the question remained, whether psychopathological findings in atopics were of pathogenetic relevance or an epiphenomenon of chronic inflammatory disease. Recently, the discussion has been revived and refocused by psychoneuroimmunological findings. We now know that atopic disease is characterized by an imbalance of the classical stress-axis response along the hypothalamus-pituitary-adrenal axis (HPA) and the sympathetic axis (SA). This imbalance can be found shoulder-to-shoulder with enhanced expression of newly emerging neuroendocrine stress mediators such as substance P (SP) and nerve growth factor that form up to a third stress axis (neurotrophin neuropeptide axis: NNA). Together they can alter the inflammatory as well as the neuroendocrine stress-response on several levels. In skin, the immediate inflammatory response to stress involves neuropeptide release and mast cell degranulation, in short neurogenic inflammation. Systemically, antigen-presentation and TH2 cytokine bias are promoted under the influence of cortisol and neuropeptides. Imbalanced stress-responsiveness may therefore be at the core of exacerbated allergic disease and deserves re-evaluation of therapeutic options such as neutralization of SP-signaling by antagonists against its receptor NK1, cortisol treatment as supplementation and relaxation techniques to balance the stress-response.
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Affiliation(s)
- Christiane Liezmann
- University-Medicine Charité; Internal Medicine and Dermatology; Department of Psychosomatic Medicine and Psychotherapy; Berlin
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27
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Tucker T, Riccardi VM, Sutcliffe M, Vielkind J, Wechsler J, Wolkenstein P, Friedman JM. Different patterns of mast cells distinguish diffuse from encapsulated neurofibromas in patients with neurofibromatosis 1. J Histochem Cytochem 2011; 59:584-90. [PMID: 21525187 PMCID: PMC3201189 DOI: 10.1369/0022155411407340] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2010] [Accepted: 03/14/2011] [Indexed: 12/14/2022] Open
Abstract
Multiple neurofibromas are cardinal features of neurofibromatosis 1 (NF1). Several different types of NF1-associated neurofibromas occur, each distinct in terms of pathological details, clinical presentation, and natural history. Mast cells are present in most neurofibromas and have been shown to be critical to the origin and progression of neurofibromas in both human NF1 and relevant mouse models. In this investigation, the authors determined whether mast cell involvement is the same for all types of NF1-associated neurofibromas. They examined the density and distribution of mast cells within 49 NF1-associated neurofibromas classified histopathologically as diffuse or encapsulated on the basis of the presence or absence of the perineurium or its constituent cells. They made two observations: (1) Diffuse neurofibromas had significantly higher densities of mast cells than did encapsulated neurofibromas, and (2) mast cells were evenly distributed throughout diffuse neurofibromas but were primarily restricted to the periphery of encapsulated neurofibromas. The differences in mast cell density and distribution differentiate the two basic types of NF1-associated neurofibromas, suggesting that the pathogenesis of diffuse and encapsulated neurofibromas may be significantly different.
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Affiliation(s)
- Tracy Tucker
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
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28
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Abstract
The importance of bidirectional brain-gut interactions in gastrointestinal (GI) illness is increasingly recognized, most prominently in the area of functional GI syndromes such as irritable bowel syndrome (IBS), functional dyspepsia, and functional chest pain. The brain receives a constant stream of interoceptive input from the GI tract, integrates this information with other interoceptive information from the body and with contextual information from the environment, and sends an integrated response back to various target cells within the GI tract. This system is optimized to assure homeostasis of the GI tract during physiological perturbations and to adapt GI function to the overall state of the organism. In health, the great majority of interoceptive information reaching the brain is not consciously perceived but serves primarily as input to autonomic reflex pathways. In patients with functional abdominal pain syndromes, conscious perception of interoceptive information from the GI tract, or recall of interoceptive memories of such input, can occur in the form of constant or recurrent discomfort or pain. This is often associated with alterations in autonomic nervous system output and with emotional changes. A model is proposed that incorporates reported peripheral and central abnormalities in patients with IBS, extrapolates similar alterations in brain-gut interactions to patients with other chronic abdominal pain syndromes, and provides novel treatment targets.
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Affiliation(s)
- Emeran A Mayer
- Center for Neurobiology of Stress, Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California, USA.
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Abstract
Mast cells are multifunctional cells that initiate not only IgE-dependent allergic diseases but also play a fundamental role in innate and adaptive immune responses to microbial infection. They are also thought to play a role in angiogenesis, tissue remodeling, wound healing, and tumor repression or growth. The broad scope of these physiologic and pathologic roles illustrates the flexible nature of mast cells, which is enabled in part by their phenotypic adaptability to different tissue microenvironments and their ability to generate and release a diverse array of bioactive mediators in response to multiple types of cell-surface and cytosolic receptors. There is increasing evidence from studies in cell cultures that release of these mediators can be selectively modulated depending on the types or groups of receptors activated. The intent of this review is to foster interest in the interplay among mast cell receptors to help understand the underlying mechanisms for each of the immunological and non-immunological functions attributed to mast cells. The second intent of this review is to assess the pathophysiologic roles of mast cells and their products in health and disease. Although mast cells have a sufficient repertoire of bioactive mediators to mount effective innate and adaptive defense mechanisms against invading microorganisms, these same mediators can adversely affect surrounding tissues in the host, resulting in autoimmune disease as well as allergic disorders.
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Affiliation(s)
- Alasdair M Gilfillan
- Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-1881, USA.
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30
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Hu H, Zhang R, Fang X, Yu M, Yu S, Zhang J, Wang H. Effects of endogenous substance P expression on degranulation in RBL-2H3 cells. Inflamm Res 2010; 60:541-6. [PMID: 21190122 DOI: 10.1007/s00011-010-0301-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2010] [Revised: 11/02/2010] [Accepted: 12/14/2010] [Indexed: 11/30/2022] Open
Abstract
OBJECTIVE AND DESIGN To determine whether RBL-2H3 cells have endogenous substance P (SP) expression under immunoglobulin E (IgE)-activated and inactivated conditions, and to ascertain the function of endogenous SP in the antigen-induced degranulation of RBL-2H3 cells. MATERIALS AND METHODS SP mRNA and protein expression in both inactivated and 2,4-dinitrophenol (DNP)-specific IgE-activated RBL-2H3 cells were assessed by real-time PCR and immunofluorescence, respectively. Following activation with DNP-specific IgE, the degranulation of RBL-2H3 cells in response to DNP-bovine serum albumin (BSA), with and without endogenous SP expression, was assessed by monitoring the release of the granular enzyme β-hexosaminidase. RESULTS Endogenous SP mRNA and peptide expression increased in activated RBL-2H3 cells, compared with inactivated RBL-2H3 cells. The small hairpin RNA (shRNA)-mediated knockdown of endogenous SP reduced the degranulation ability of RBL-2H3 cells. CONCLUSIONS Activated RBL-2H3 cells express endogenous SP which plays a role in antigen-induced degranulation.
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Affiliation(s)
- Hua Hu
- Department of ENT, Huadong Hospital, Shanghai Medical School, Fudan University, Shanghai, 200032, People's Republic of China
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31
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Burnstock G, Fredholm BB, North RA, Verkhratsky A. The birth and postnatal development of purinergic signalling. Acta Physiol (Oxf) 2010; 199:93-147. [PMID: 20345419 DOI: 10.1111/j.1748-1716.2010.02114.x] [Citation(s) in RCA: 102] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The purinergic signalling system is one of the most ancient and arguably the most widespread intercellular signalling system in living tissues. In this review we present a detailed account of the early developments and current status of purinergic signalling. We summarize the current knowledge on purinoceptors, their distribution and role in signal transduction in various tissues in physiological and pathophysiological conditions.
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Affiliation(s)
- G Burnstock
- Autonomic Neuroscience Centre, Royal Free and University College Medical School, London, UK.
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32
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Pundir P, Kulka M. The role of G protein‐coupled receptors in mast cell activation by antimicrobial peptides: is there a connection? Immunol Cell Biol 2010; 88:632-40. [DOI: 10.1038/icb.2010.27] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Affiliation(s)
- Priyanka Pundir
- National Research Council‐Institute for Nutrisciences and Health Charlottetown Prince Edward Island Canada
- Department of Biomedical Sciences, Atlantic Veterinary College, University of PEI Charlottetown Prince Edward Island Canada
| | - Marianna Kulka
- National Research Council‐Institute for Nutrisciences and Health Charlottetown Prince Edward Island Canada
- Department of Biomedical Sciences, Atlantic Veterinary College, University of PEI Charlottetown Prince Edward Island Canada
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Substance P downregulates expression of the high affinity IgE receptor (FcepsilonRI) by human mast cells. J Neuroimmunol 2010; 220:17-24. [PMID: 20117843 DOI: 10.1016/j.jneuroim.2009.12.006] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2009] [Revised: 12/07/2009] [Accepted: 12/07/2009] [Indexed: 01/09/2023]
Abstract
The effect of the neuropeptide substance P (SP) on human mast cell (MC) phenotype is poorly understood. In this study, SP effects on human MC expression of the high affinity IgE receptor (FcepsilonRI) were characterized. SP downregulated expression of FcepsilonRI mRNA and protein by approximately 50% and in a concentration dependent manner, the effect was partially mediated by engagement of the neurokinin-1 receptor (NK1R) and resulted in reduced mast cell activation. Sensitization of MC with IgE prior to SP exposure protected MC from SP-mediated FcepsilonRI downregulation. SP release may inhibit MC responses to allergens and these results may have implications in neuroinflammatiion and stress.
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34
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Vempati R, Bijlani RL, Deepak KK. The efficacy of a comprehensive lifestyle modification programme based on yoga in the management of bronchial asthma: a randomized controlled trial. BMC Pulm Med 2009; 9:37. [PMID: 19643002 PMCID: PMC2734746 DOI: 10.1186/1471-2466-9-37] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2008] [Accepted: 07/30/2009] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND There is a substantial body of evidence on the efficacy of yoga in the management of bronchial asthma. Many studies have reported, as the effects of yoga on bronchial asthma, significant improvements in pulmonary functions, quality of life and reduction in airway hyper-reactivity, frequency of attacks and medication use. In addition, a few studies have attempted to understand the effects of yoga on exercise-induced bronchoconstriction (EIB) or exercise tolerance capacity. However, none of these studies has investigated any immunological mechanisms by which yoga improves these variables in bronchial asthma. METHODS The present randomized controlled trial (RCT) was conducted on 57 adult subjects with mild or moderate bronchial asthma who were allocated randomly to either the yoga (intervention) group (n = 29) or the wait-listed control group (n = 28). The control group received only conventional care and the yoga group received an intervention based on yoga, in addition to the conventional care. The intervention consisted of 2-wk supervised training in lifestyle modification and stress management based on yoga followed by closely monitored continuation of the practices at home for 6-wk. The outcome measures were assessed in both the groups at 0 wk (baseline), 2, 4 and 8 wk by using Generalized Linear Model (GLM) repeated measures followed by post-hoc analysis. RESULTS In the yoga group, there was a steady and progressive improvement in pulmonary function, the change being statistically significant in case of the first second of forced expiratory volume (FEV1) at 8 wk, and peak expiratory flow rate (PEFR) at 2, 4 and 8 wk as compared to the corresponding baseline values. There was a significant reduction in EIB in the yoga group. However, there was no corresponding reduction in the urinary prostaglandin D2 metabolite (11beta prostaglandin F2alpha) levels in response to the exercise challenge. There was also no significant change in serum eosinophilic cationic protein levels during the 8-wk study period in either group. There was a significant improvement in Asthma Quality of Life (AQOL) scores in both groups over the 8-wk study period. But the improvement was achieved earlier and was more complete in the yoga group. The number-needed-to-treat worked out to be 1.82 for the total AQOL score. An improvement in total AQOL score was greater than the minimal important difference and the same outcome was achieved for the sub-domains of the AQOL. The frequency of rescue medication use showed a significant decrease over the study period in both the groups. However, the decrease was achieved relatively earlier and was more marked in the yoga group than in the control group. CONCLUSION The present RCT has demonstrated that adding the mind-body approach of yoga to the predominantly physical approach of conventional care results in measurable improvement in subjective as well as objective outcomes in bronchial asthma. The trial supports the efficacy of yoga in the management of bronchial asthma. However, the preliminary efforts made towards working out the mechanism of action of the intervention have not thrown much light on how yoga works in bronchial asthma. TRIAL REGISTRATION Current Controlled Trials ISRCTN00815962.
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Affiliation(s)
- Ramaprabhu Vempati
- Department of Physiology, All India Institute of Medical Sciences, New Delhi, India
| | - Ramesh Lal Bijlani
- Department of Physiology, All India Institute of Medical Sciences, New Delhi, India
- Sri Aurobindo Ashram, New Delhi, India
| | - Kishore Kumar Deepak
- Department of Physiology, All India Institute of Medical Sciences, New Delhi, India
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Cyphert JM, Kovarova M, Allen IC, Hartney JM, Murphy DL, Wess J, Koller BH. Cooperation between mast cells and neurons is essential for antigen-mediated bronchoconstriction. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2009; 182:7430-9. [PMID: 19494266 PMCID: PMC3901060 DOI: 10.4049/jimmunol.0900039] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Mast cells are important sentinels guarding the interface between the environment and the body: a breach in the integrity of this interface can lead to the release of a plethora of mediators that engage the foreign agent, recruit leukocytes, and initiate adaptive physiological changes in the organism. While these capabilities make mast cells critical players in immune defense, it also makes them important contributors to the pathogenesis of diseases such as asthma. Mast cell mediators induce dramatic changes in smooth muscle physiology, and the expression of receptors for these factors by smooth muscle suggests that they act directly to initiate constriction. Contrary to this view, we show herein that mast cell-mediated bronchoconstriction is observed only in animals with intact innervation of the lung and that serotonin release alone is required for this action. While ablation of sensory neurons does not limit bronchoconstriction, constriction after Ag challenge is absent in mice in which the cholinergic pathways are compromised. Linking mast cell function to the cholinergic system likely provides an important means of modulating the function of these resident immune cells to physiology of the lung, but may also provide a safeguard against life-threatening anaphylaxis during mast cell degranulation.
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Affiliation(s)
- Jaime M Cyphert
- Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
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Siebenhaar F, Magerl M, Peters EM, Hendrix S, Metz M, Maurer M. Mast cell–driven skin inflammation is impaired in the absence of sensory nerves. J Allergy Clin Immunol 2008; 121:955-61. [DOI: 10.1016/j.jaci.2007.11.013] [Citation(s) in RCA: 65] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2007] [Revised: 11/13/2007] [Accepted: 11/15/2007] [Indexed: 12/26/2022]
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Amano H, Negishi I, Akiyama H, Ishikawa O. Psychological stress can trigger atopic dermatitis in NC/Nga mice: an inhibitory effect of corticotropin-releasing factor. Neuropsychopharmacology 2008; 33:566-73. [PMID: 17460609 DOI: 10.1038/sj.npp.1301435] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Atopic dermatitis (AD) is one of the most common inflammatory diseases of the skin and is usually associated with a family history of atopic diathesis. It has been well established that many environmental or psychological factors aggravate AD. However, it is not clear whether psychological stress by itself can trigger AD. We examined the effect of psychological stress on the onset of AD, using an animal model, the NC/Nga mouse. The animals were exposed to the water avoidance stress (WAS) test to induce psychological stress. Additionally, we examined how corticotropin-releasing factor (CRF) affected the development of AD induced by psychological stress. Under specific pathogen-free (SPF) conditions, NC/Nga mice did not develop AD-like skin lesions. In contrast, NC/Nga mice exposed to psychological stress developed AD-like skin lesions along with elevated levels of serum immunoglobulin E even when kept under SPF conditions. The AD-like skin lesions induced by WAS were completely blocked by pretreating the animals with CRF. Our data indicate that a psychological factor is capable of eliciting AD-like skin lesions in NC/Nga mice. It is possible that the inhibitory effect of CRF may be mediated by the functional modification of various cells that have CRF receptors.
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Affiliation(s)
- Hiroo Amano
- Department of Dermatology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
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Wang J, Hauer-Jensen M. Neuroimmune interactions: potential target for mitigating or treating intestinal radiation injury. Br J Radiol 2007; 80 Spec No 1:S41-8. [PMID: 17704325 DOI: 10.1259/bjr/33057885] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Intestinal radiation injury is characterized by breakdown of the epithelial barrier and mucosal inflammation. In addition to replicative and apoptotic cell death, radiation also induces changes in cellular function, as well as alterations secondary to tissue injury. The recognition of these "non-cytocidal" radiation effects has enhanced the understanding of normal tissue radiation toxicity, thus allowing an integrated systems biology-based approach to modulating radiation responses and providing a mechanistic rationale for interventions to mitigate or treat radiation injuries. The enteric nervous system regulates intestinal motility, blood flow and enterocyte function. The enteric nervous system also plays a central role in maintaining the physiological state of the intestinal mucosa and in coordinating inflammatory and fibroproliferative processes. The afferent component of the enteric nervous system, in addition to relaying sensory information, also exerts important effector functions and contributes critically to preserving mucosal integrity. Interactions between afferent nerves, mast cells as well as other cells of the resident mucosal immune system serve to maintain mucosal homeostasis and to ensure an appropriate response to injury. Notably, enteric sensory neurons regulate the activation threshold of mast cells by secreting substance P, calcitonin gene-related peptide and other neuropeptides, whereas mast cells signal to enteric nerves by the release of histamine, nerve growth factor and other mediators. This article reviews how enteric neurons interact with mast cells and other immune cells to regulate the intestinal radiation response and how these interactions may be modified to mitigate intestinal radiation toxicity. These data are not only applicable to radiation therapy, but also to intestinal injury in a radiological terrorism scenario.
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Affiliation(s)
- J Wang
- Department of Surgery, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, AR 72205, USA
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Kulka M, Sheen CH, Tancowny BP, Grammer LC, Schleimer RP. Neuropeptides activate human mast cell degranulation and chemokine production. Immunology 2007; 123:398-410. [PMID: 17922833 DOI: 10.1111/j.1365-2567.2007.02705.x] [Citation(s) in RCA: 326] [Impact Index Per Article: 18.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
During neuronal-induced inflammation, mast cells may respond to stimuli such as neuropeptides in an FcepsilonRI-independent manner. In this study, we characterized human mast cell responses to substance P (SP), nerve growth factor (NGF), calcitonin gene-related peptide (CGRP) and vasoactive intestinal polypeptide (VIP) and compared these responses to human mast cell responses to immunoglobulin E (IgE)/anti-IgE and compound 48/80. Primary cultured mast cells, generated from CD34(+) progenitors in the presence of stem cell factor and interleukin-6 (IL-6), and human cultured mast cells (LAD2) were stimulated with these and other stimuli (gastrin, concanavalin A, radiocontrast media, and mannitol) and their degranulation and chemokine production was assessed. VIP and SP stimulated primary human mast cells and LAD cells to degranulate; gastrin, concanavalin A, radiocontrast media, mannitol, CGRP and NGF did not activate degranulation. While anti-IgE stimulation did not induce significant production of chemokines, stimulation with VIP, SP or compound 48/80 potently induced production of monocyte chemoattractant protein-1, inducible protein-10, monokine induced by interferon-gamma (MIG), RANTES (regulated on activation, normal, T-cell expressed, and secreted) and IL-8. VIP, SP and compound 48/80 also activated release of tumour necrosis factor, IL-3 and granulocyte-macrophage colony-stimulating factor, but not IL-4, interferon-gamma or eotaxin. Human mast cells expressed surface neurokinin 1 receptor (NK1R), NK2R, NK3R and VIP receptor type 2 (VPAC2) but not VPAC1 and activation of human mast cells by IgE/anti-IgE up-regulated expression of VPAC2, NK2R, and NK3R. These studies demonstrate the pattern of receptor expression and activation of mast cell by a host of G-protein coupled receptor ligands and suggest that SP and VIP activate a unique signalling pathway in human mast cells. These results are likely to have direct relevance to neuronally induced inflammatory diseases.
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Affiliation(s)
- Marianna Kulka
- National Research Council Canada, Room 432, 550 University Avenue, Charlottetown, PE, Canada.
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40
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Costa-Pinto FA, Basso AS, Russo M. Role of mast cell degranulation in the neural correlates of the immediate allergic reaction in a murine model of asthma. Brain Behav Immun 2007; 21:783-90. [PMID: 17291717 DOI: 10.1016/j.bbi.2007.01.002] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2006] [Revised: 01/03/2007] [Accepted: 01/03/2007] [Indexed: 11/15/2022] Open
Abstract
Experimental airway allergy in mice leads to increased activity in specific hypothalamic and amygdaloid nuclei, and behavioral changes. The experiments described here were designed to determine the role of anaphylactic antibodies, mast cell degranulation, and lung inflammation in the neural and behavioral correlates of an experimental murine asthma-like response. Animals were sensitized intraperitoneally with ovalbumin adsorbed to alum, and challenged by intranasal ovalbumin instillation or aerosol. To induce immunological tolerance, animals were fed ovalbumin in the drinking water for 5 consecutive days, along with primary sensitization. Depletion of IgE was also accomplished with a non-anaphylactic anti-IgE antibody. Mast cell degranulation was inhibited by cromolyn. In addition to BALB/c animals, C3H/HeJ mice were used for their relative resistance to lung allergic inflammation. We confirmed that ovalbumin challenge in allergic mice leads to increased activity in the paraventricular nucleus of the hypothalamus and central nucleus of the amygdala, and avoidance behavior towards an allergen-associated compartment. Moreover, these responses were precluded by oral tolerance or anti-IgE treatment, even in the presence of IgG1. Cromolyn abrogates both responses in the presence of anaphylactic antibodies. Finally, although sensitized C3H/HeJ mice did not develop airway inflammation, they exhibited brain and behavioral changes similar to BALB/c animals. The repercussions of murine allergic asthma on brain and behavior are IgE-dependent, mediated by mast cell degranulation, and do not require a pulmonary inflammatory infiltrate, suggesting that the early phase of this immediate allergic response suffices for the brain activation associated with avoidance behavior towards exposure to the allergen.
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41
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Rijnierse A, Nijkamp FP, Kraneveld AD. Mast cells and nerves tickle in the tummy: implications for inflammatory bowel disease and irritable bowel syndrome. Pharmacol Ther 2007; 116:207-35. [PMID: 17719089 DOI: 10.1016/j.pharmthera.2007.06.008] [Citation(s) in RCA: 85] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2007] [Accepted: 06/20/2007] [Indexed: 12/12/2022]
Abstract
Mast cells are well known as versatile cells capable of releasing and producing a variety of inflammatory mediators upon activation and are often found in close proximity of neurons. In addition, inflammation leads to local activation of neurons resulting in the release neuropeptides, which also play an important immune modulatory role by stimulation of immune cells. In intestinal disorders like inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS), the number of mast cells is known to be much higher than in the normal intestine. Moreover, both these disorders are also reported to be associated with alterations in neuropeptide content and in neural innervation. Mutual association between mast cells and enteric nerves has been demonstrated to be increased in pathophysiological conditions and contribute to spreading and amplification of the response in IBD and IBS. In this review the focus lies on studies appointed to the direct interaction between mast cells and nerves in IBD, IBS, and animal models for these disorders so far.
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Affiliation(s)
- Anneke Rijnierse
- Department of Pharmacology and Pathophysiology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, The Netherlands.
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Abstract
This review is focused on purinergic neurotransmission, i.e., ATP released from nerves as a transmitter or cotransmitter to act as an extracellular signaling molecule on both pre- and postjunctional membranes at neuroeffector junctions and synapses, as well as acting as a trophic factor during development and regeneration. Emphasis is placed on the physiology and pathophysiology of ATP, but extracellular roles of its breakdown product, adenosine, are also considered because of their intimate interactions. The early history of the involvement of ATP in autonomic and skeletal neuromuscular transmission and in activities in the central nervous system and ganglia is reviewed. Brief background information is given about the identification of receptor subtypes for purines and pyrimidines and about ATP storage, release, and ectoenzymatic breakdown. Evidence that ATP is a cotransmitter in most, if not all, peripheral and central neurons is presented, as well as full accounts of neurotransmission and neuromodulation in autonomic and sensory ganglia and in the brain and spinal cord. There is coverage of neuron-glia interactions and of purinergic neuroeffector transmission to nonmuscular cells. To establish the primitive and widespread nature of purinergic neurotransmission, both the ontogeny and phylogeny of purinergic signaling are considered. Finally, the pathophysiology of purinergic neurotransmission in both peripheral and central nervous systems is reviewed, and speculations are made about future developments.
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Affiliation(s)
- Geoffrey Burnstock
- Autonomic Neurscience Centre, Royal Free and University College Medical School, London, UK.
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43
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Burnstock G. Non-synaptic transmission at autonomic neuroeffector junctions. Neurochem Int 2007; 52:14-25. [PMID: 17493707 DOI: 10.1016/j.neuint.2007.03.007] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2007] [Accepted: 03/30/2007] [Indexed: 10/23/2022]
Abstract
Non-synaptic transmission is characteristic of autonomic neuroeffector junctions. The structure of the autonomic neuromuscular junction is described. The essential features are that: the terminal portions of autonomic nerve fibers are varicose and mobile, transmitters being released 'en passage' from varying distances from the effector cells; while there is no structural post-junctional specialization on effector cells, receptors for neurotransmitters accumulate on cell membranes at close junctions; muscle effectors are bundles rather than single smooth muscle cells, that are connected by gap junctions which allow electrotonic spread of activity between cells. A multiplicity of transmitters are utilized by autonomic nerves, and cotransmission occurs often involving synergistic actions of the cotransmitters, although pre- and post-junctional neuromodulation of neurotransmitter release also take place. It is suggested that autonomic neural control of immune, epithelial and endothelial cells also involves non-synaptic transmission.
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Affiliation(s)
- Geoffrey Burnstock
- Autonomic Neuroscience Centre, Royal Free and University College School of Medicine, Rowland Hill Street, London NW3 2PF, United Kingdom.
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Gilja OH, Hatlebakk JG, Odegaard S, Berstad A, Viola I, Giertsen C, Hausken T, Gregersen H. Advanced imaging and visualization in gastrointestinal disorders. World J Gastroenterol 2007; 13:1408-21. [PMID: 17457973 PMCID: PMC4146926 DOI: 10.3748/wjg.v13.i9.1408] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Advanced medical imaging and visualization has a strong impact on research and clinical decision making in gastroenterology. The aim of this paper is to show how imaging and visualization can disclose structural and functional abnormalities of the gastrointestinal (GI) tract. Imaging methods such as ultrasonography, magnetic resonance imaging (MRI), endoscopy, endosonography, and elastography will be outlined and visualization with Virtual Reality and haptic methods. Ultrasonography is a versatile method that can be used to evaluate antral contractility, gastric emptying, transpyloric flow, gastric configuration, intragastric distribution of meals, gastric accommodation and strain measurement of the gastric wall. Advanced methods for endoscopic ultrasound, three-dimensional (3D) ultrasound, and tissue Doppler (Strain Rate Imaging) provide detailed information of the GI tract. Food hypersensitivity reactions including gastrointestinal reactions due to food allergy can be visualized by ultrasonography and MRI. Development of multi-parametric and multi-modal imaging may increase diagnostic benefits and facilitate fusion of diagnostic and therapeutic imaging in the future.
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Affiliation(s)
- Odd Helge Gilja
- National Centre for Ultrasound in Gastroenterology, Department of Medicine, Haukeland University Hospital, Bergen N-5021, Norway.
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Kakurai M, Monteforte R, Suto H, Tsai M, Nakae S, Galli SJ. Mast cell-derived tumor necrosis factor can promote nerve fiber elongation in the skin during contact hypersensitivity in mice. THE AMERICAN JOURNAL OF PATHOLOGY 2006; 169:1713-21. [PMID: 17071594 PMCID: PMC1780201 DOI: 10.2353/ajpath.2006.060602] [Citation(s) in RCA: 69] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
In humans, lesions of contact eczema or atopic dermatitis can exhibit increases in epidermal nerves, but the mechanism resulting in such nerve elongation are not fully understood. We found that contact hypersensitivity reactions to oxazolone in mice were associated with significant increases in the length of nerves in the epidermis and dermis. Using genetically mast cell-deficient c-kit mutant mice selectively repaired of their dermal mast cell deficiency with either wild-type or tumor necrosis factor (TNF)-deficient mast cells, we found that mast cells, and mast cell-derived TNF, significantly contributed to the elongation of epidermal and dermal PGP 9.5+ nerves and dermal CGRP+ nerves, as well as to the inflammation observed at sites of contact hypersensitivity in response to oxazolone. Moreover, the percentage of mast cells in close proximity to dermal PGP 9.5+ nerve fibers was significantly higher in wild-type mice and in c-kit mutant mice repaired of their dermal mast cell deficiency by the adoptive transfer of wild-type mast cells than in TNF-deficient mice or in TNF-/- mast cell-engrafted c-kit mutant mice. These observations show that mast cells, and mast cell-derived TNF, can promote the elongation of cutaneous nerve fibers during contact hypersensitivity in the mouse.
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Affiliation(s)
- Maki Kakurai
- Department of Pathology, L-235, Stanford University School of Medicine, 300 Pasteur Dr., Stanford, CA 94305-5324, USA
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Wang J, Zheng H, Kulkarni A, Ou X, Hauer-Jensen M. Regulation of early and delayed radiation responses in rat small intestine by capsaicin-sensitive nerves. Int J Radiat Oncol Biol Phys 2006; 64:1528-36. [PMID: 16580503 DOI: 10.1016/j.ijrobp.2005.12.035] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2005] [Revised: 12/22/2005] [Accepted: 12/22/2005] [Indexed: 10/24/2022]
Abstract
PURPOSE Mast cells protect against the early manifestations of intestinal radiation toxicity, but promote chronic intestinal wall fibrosis. Intestinal sensory nerves are closely associated with mast cells, both anatomically and functionally, and serve an important role in the regulation of mucosal homeostasis. This study examined the effect of sensory nerve ablation on the intestinal radiation response in an established rat model. METHODS AND MATERIALS Rats underwent sensory nerve ablation with capsaicin or sham ablation. Two weeks later, a localized segment of ileum was X-irradiated or sham irradiated. Structural, cellular, and molecular changes were examined 2 weeks (early injury) and 26 weeks (chronic injury) after irradiation. The mast cell dependence of the effect of sensory nerve ablation on intestinal radiation injury was assessed using c-kit mutant (Ws/Ws) mast cell-deficient rats. RESULTS Capsaicin treatment caused a baseline reduction in mucosal mast cell density, crypt cell proliferation, and expression of substance P and calcitonin gene-related peptide, two neuropeptides released by sensory neurons. Sensory nerve ablation strikingly exacerbated early intestinal radiation toxicity (loss of mucosal surface area, inflammation, intestinal wall thickening), but attenuated the development of chronic intestinal radiation fibrosis (collagen I accumulation and transforming growth factor beta immunoreactivity). In mast cell-deficient rats, capsaicin treatment exacerbated postradiation epithelial injury (loss of mucosal surface area), but none of the other aspects of radiation injury were affected by capsaicin treatment. CONCLUSIONS Ablation of capsaicin-sensitive enteric neurons exacerbates early intestinal radiation toxicity, but attenuates development of chronic fibroproliferative changes. The effect of capsaicin treatment on the intestinal radiation response is partly mast cell dependent.
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Affiliation(s)
- Junru Wang
- Department of Surgery, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, AR 72205, USA
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47
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PETERSEN LJ, WINGE K, BRODIN E, SKOV PS. No release of histamine and substance P in capsaicin-induced neurogenic inflammation in intact human skin in vivo:
a microdialysis study. Clin Exp Allergy 2006. [DOI: 10.1111/j.1365-2222.1997.tb01239.x] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Nassenstein C, Schulte-Herbrüggen O, Renz H, Braun A. Nerve growth factor: the central hub in the development of allergic asthma? Eur J Pharmacol 2006; 533:195-206. [PMID: 16458292 DOI: 10.1016/j.ejphar.2005.12.061] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/13/2005] [Indexed: 01/19/2023]
Abstract
Neurotrophins like nerve growth factor (NGF), originally described as nerve growth factors in neuronal development, have been implicated in many physiological processes in the last years. They are now regarded as important factors involved in the resolution of pathological conditions. NGF has profound effects on inflammation, repair and remodeling of tissues. However, in the lung these beneficial effects can transact into disease promoting actions, e.g., in allergic inflammation or respiratory syncytial virus (RSV) infection. Overproduction of NGF then enhances inflammation, and promotes (neuronal) airway hyperreactivity and neurogenic inflammation. We hypothesize that NGF overexpression in certain vulnerable time windows during infancy could be a major risk factor for the development of asthma symptoms.
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Affiliation(s)
- Christina Nassenstein
- Fraunhofer Institute of Toxicology and Experimental Medicine, 30625 Hannover, and Department of Clinical Chemistry and Molecular Diagnostics, Hospital of the Philipps University, Marburg, Germany
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Lettesjö H, Hansson T, Peterson C, Ung KA, Ringström G, Abrahamsson H, Simrén M. Detection of inflammatory markers in stools from patients with irritable bowel syndrome and collagenous colitis. Scand J Gastroenterol 2006; 41:54-9. [PMID: 16373277 DOI: 10.1080/00365520510023909] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
OBJECTIVE Irritable bowel syndrome (IBS) and collagenous colitis (CC) share chronically recurring symptoms of altered bowel habits associated with abdominal pain or discomfort. The aims of the present study were to investigate whether inflammatory markers could be detected in faeces from patients with IBS and CC, and to elucidate whether such analyses could be used as non-invasive tools to distinguish between these disorders. MATERIAL AND METHODS Stool samples were obtained from 18 patients with CC, 46 patients with IBS and 20 healthy controls (HC). Eosinophil protein X (EPX), myeloperoxidase (MPO), tryptase, interleukin-1 beta (IL-1beta) and tumour necrosis factor alpha (TNFalpha) were measured in supernatants from processed faeces using immunoassays. RESULTS EPX levels were enhanced in faeces from CC patients (median 3.8 microg/g (0.47-16.2)) compared to patients with IBS (0.44 microg/g (0.25-1.8)), p<0.001, and HC (0.46 microg/g (0.21-1.3)), p<0.001. In addition, MPO was increased in CC patients (11.7 microg/g (2.0-124)) compared to IBS patients (1.7 microg/g (0.81-5.2)), p<0.01, and HC (2.5 microg/g (1.1-6.3)), p<0.05. Tryptase was found in 9/18 patients with CC, 6/46 with IBS and 1/19 HC. IL-1beta was only enhanced in 2/11 CC patients and TNFalpha was not detected in any sample. CONCLUSIONS Increased levels of EPX, MPO and tryptase were observed in stools from collagenous colitis patients, whereas the levels in IBS patients did not differ from healthy controls. Our data suggest that faecal markers could be used as part of the clinical work-up to determine which patients should be biopsied and evaluated for collagenous colitis.
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Affiliation(s)
- Helene Lettesjö
- Department of Gastrointestinal Research, Pharmacia Diagnostics, Uppsala, Sweden
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Berstad A, Arslan G, Lind R, Florvaag E. Food hypersensitivity-immunologic (peripheral) or cognitive (central) sensitisation? Psychoneuroendocrinology 2005; 30:983-9. [PMID: 15979811 DOI: 10.1016/j.psyneuen.2005.04.010] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2004] [Revised: 03/30/2005] [Accepted: 04/01/2005] [Indexed: 01/01/2023]
Abstract
Patients with food hypersensitivity suffer poor quality of life and several unexplained health complaints, both abdominal and extra-abdominal. Part of the suffering is due to healthcare providers' neglect and poor insight, allowing a strong position for alternative medicine. Distinguishing food allergy from functional and organic disorders can be extremely difficult. We have found examination of faecal calprotectin and gut permeability to be useful for excluding organic disease, whilst conventional provocation tests for positive diagnosis of food hypersensitivity are cumbersome. Our new ultrasound provocation test has been promising, but we acknowledge that much work remains to be done before its sensitivity and specificity can be finally established. The majority of patients with self-reported food hypersensitivity have a non-allergic hypersensitivity disorder. We suggest that cognitive-emotional sensitisation at the brain level, and not peripheral (immunological) sensitisation, is a major pathogenetic mechanism by which the patients' various abdominal and extra-abdominal health complaints are generated. Extensive activation of cognitive networks might be triggered by peripheral sensory mechanisms, often misinterpreted as 'food allergy'. Clearly, the approach to patients with food hypersensitivity should be interdisciplinary.
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Affiliation(s)
- Arnold Berstad
- Division of Gastroenterology, Institute of Medicine, Haukeland University Hospital, 5021 Bergen, Norway.
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