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Sutradhar S, Ali H. Mast cell MrgprB2 in neuroimmune interaction in IgE-mediated airway inflammation and its modulation by β-arrestin2. Front Immunol 2024; 15:1470016. [PMID: 39483467 PMCID: PMC11524863 DOI: 10.3389/fimmu.2024.1470016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Accepted: 09/25/2024] [Indexed: 11/03/2024] Open
Abstract
Introduction Allergic asthma has been linked to the activation of mast cells (MCs) by the neuropeptide substance P (SP), but the mechanism underlying this neuroimmune interaction is unknown. Substance P produced from cutaneous nociceptors activates MCs via Mas-related G-protein-coupled receptor B2 (MrgprB2) to enhance type 2 immune response in experimental atopic dermatitis in mice. We recently showed that the adapter protein β-arrestin2 (β-arr2) contributes to MrgprB2-mediated MC chemotaxis. The goals of this study were to determine if MrgprB2 facilitates neuroimmune interaction in IgE (FcεRI)-mediated allergic airway inflammation (AAI) and to assess if this response is modulated by β-arr2. Methods Wild-type (WT), MrgprB2-/- mice and mice with MC-specific deletion of β-arr2 (Cpa3Cre+ /β-arr2fl/fl ) were passively sensitized with anti-TNP-IgE and challenged with antigen. The generation of SP and MC recruitment in the lung were determined by immunofluorescence and toluidine blue staining, respectively. The transcripts for Tac1, MrgprB2, TNF-α, and Th2 cytokines in lung tissue were assessed by RT-PCR, and the release of selected cytokines in bronchoalveolar lavage (BAL) was determined by ELISA. Eosinophil and neutrophil recruitment in lung tissue and BAL were determined by immunofluorescence staining and flow cytometry, respectively. Goblet cell hyperplasia was determined by periodic acid-Schiff staining. Results Following IgE sensitization and antigen challenge in WT mice, SP generation, and MC recruitment, transcripts for Tac1, MrgprB2, TNF-α, and Th2 cytokine were upregulated when compared to the control challenge. TNF-α, Th2 cytokine production, eosinophil/neutrophil recruitment, and goblet cell hyperplasia were also increased. These responses were significantly reduced in MrgprB2-/- and Cpa3Cre+ /β-arr2fl/fl mice. Discussion The data presented herein suggest that SP-mediated MrgprB2 activation contributes to AAI and goblet cell hyperplasia in mice. Furthermore, these responses are modulated by β-arr2, which promotes MC recruitment to facilitate their activation through FcεRI.
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Affiliation(s)
| | - Hydar Ali
- Department of Basic and Translational Sciences, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, United States
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Ritondo BL, Rogliani P, Facciolo F, Falco S, Vocale A, Calzetta L. Beclomethasone dipropionate and sodium cromoglycate protect against airway hyperresponsiveness in a human ex vivo model of cow's milk aspiration. CURRENT RESEARCH IN PHARMACOLOGY AND DRUG DISCOVERY 2021; 2:100010. [PMID: 34909646 PMCID: PMC8663930 DOI: 10.1016/j.crphar.2020.100010] [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: 09/07/2020] [Revised: 11/24/2020] [Accepted: 11/27/2020] [Indexed: 11/29/2022] Open
Abstract
Background Recurrent cow's milk (CM) aspiration is often associated with gastroesophageal reflux in infants and toddlers and it seems to be implicated in the etiology of different inflammatory lung disorders. This study aimed to investigate ex vivo the impact of CM aspiration on human airways and whether treatment with beclomethasone dipropionate (BDP) or sodium cromoglycate (SCG) may prevent the potential CM-induced airway hyperresponsiveness (AHR). Methods Human isolated bronchi were contracted by electrical field stimulation (EFS10Hz) to mimic the contractile tone induced by the parasympathetic activity and challenged with CM, fat/lactose-free CM, or human breast milk (HM). The effect of pre-treatment with beclomethasone dipropionate (BDP) and sodium cromoglycate (SCG) was also investigated on the AHR induced by CM. Results After a 60 min-challenge with CM 1:10 v/v and fat/lactose-free CM 1:10 v/v, ASM significantly (P < 0.05) increased compared to control (+67.04 ± 17.08% and +77.91 ± 1.34%, respectively), a condition that remained stable for 150 min post-treatment, whereas HM did not alter ASM contractility. BDP 1 μM and 10 μM significantly (P < 0.05) reduced the AHR elicited by CM (−52.49 ± 10.97% and −66.98 ± 7.90%, respectively vs. control). At the same manner, SCG 1 μM and 10 μM significantly (P < 0.05) inhibited the CM-induced AHR (−59.03 ± 9.24% and −73.52 ± 7.41%, respectively vs. control). Conclusion CM induces AHR in human ASM by eliciting an increased parasympathetic contractile response. Preventive treatment with nebulized SCG may be indicated in infants or toddlers fed with CM, rather than with BDP due to a superior safety profile.
Cow's milk aspiration seems to be associated with some inflammatory lung diseases. Cow's milk aspiration induces human airway hyperresponsiveness. Beclomethasone and sodium cromoglycate protect against cow's milk hyperresponsiveness in vitro. Inhaled sodium cromoglycate might be suitable in children at risk of cow's milk aspiration.
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Affiliation(s)
- Beatrice Ludovica Ritondo
- Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome "Tor Vergata", Via Montpellier 1, 00133, Rome, Italy
| | - Paola Rogliani
- Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome "Tor Vergata", Via Montpellier 1, 00133, Rome, Italy
| | - Francesco Facciolo
- Thoracic Surgery Unit, Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy
| | - Silvia Falco
- Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome "Tor Vergata", Via Montpellier 1, 00133, Rome, Italy
| | - Aurora Vocale
- Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome "Tor Vergata", Via Montpellier 1, 00133, Rome, Italy
| | - Luigino Calzetta
- Department of Medicine and Surgery, Respiratory Disease and Lung Function Unit, University of Parma, Via Rasori 10, 43126, Parma, Italy
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Thapaliya M, Chompunud Na Ayudhya C, Amponnawarat A, Roy S, Ali H. Mast Cell-Specific MRGPRX2: a Key Modulator of Neuro-Immune Interaction in Allergic Diseases. Curr Allergy Asthma Rep 2021; 21:3. [PMID: 33398613 DOI: 10.1007/s11882-020-00979-5] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/26/2020] [Indexed: 12/13/2022]
Abstract
PURPOSE OF REVIEW Atopic dermatitis (AD) and allergic asthma are complex disorders with significant public health burden. This review provides an overview of the recent developments on Mas-related G protein-coupled receptor-X2 (MRGPRX2; mouse counterpart MrgprB2) as a potential candidate to target neuro-immune interaction in AD and allergic asthma. RECENT FINDINGS Domestic allergens directly activate sensory neurons to release substance P (SP), which induces mast cell degranulation via MrgprB2 and drives type 2 skin inflammation in AD. MRGPRX2 expression is upregulated in human lung mast cells and serum of asthmatic patients. Both SP and hemokinin-1 (HK-1 generated from macrophages, bronchial cells, and mast cells) cause degranulation of human mast cells via MRGPRX2. MrgprB2 contributes to mast cell-nerve interaction in the pathogenesis of AD. Furthermore, asthma severity is associated with increased MRGPRX2 expression in mast cells. Thus, MRGPRX2 could serve as a novel target for modulating AD and asthma.
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Affiliation(s)
- Monica Thapaliya
- Department of Basic and Translational Sciences, University of Pennsylvania, School of Dental Medicine, Philadelphia, PA, 19104, USA
| | - Chalatip Chompunud Na Ayudhya
- Department of Basic and Translational Sciences, University of Pennsylvania, School of Dental Medicine, Philadelphia, PA, 19104, USA
| | - Aetas Amponnawarat
- Department of Basic and Translational Sciences, University of Pennsylvania, School of Dental Medicine, Philadelphia, PA, 19104, USA
| | - Saptarshi Roy
- Department of Basic and Translational Sciences, University of Pennsylvania, School of Dental Medicine, Philadelphia, PA, 19104, USA
| | - Hydar Ali
- Department of Basic and Translational Sciences, University of Pennsylvania, School of Dental Medicine, Philadelphia, PA, 19104, USA.
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Le Floc’h A, Allinne J, Nagashima K, Scott G, Birchard D, Asrat S, Bai Y, Lim WK, Martin J, Huang T, Potocky TB, Kim JH, Rafique A, Papadopoulos NJ, Stahl N, Yancopoulos GD, Murphy AJ, Sleeman MA, Orengo JM. Dual blockade of IL-4 and IL-13 with dupilumab, an IL-4Rα antibody, is required to broadly inhibit type 2 inflammation. Allergy 2020; 75:1188-1204. [PMID: 31838750 PMCID: PMC7317958 DOI: 10.1111/all.14151] [Citation(s) in RCA: 299] [Impact Index Per Article: 59.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Revised: 10/30/2019] [Accepted: 11/12/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND Dupilumab, a fully human monoclonal antibody that binds IL-4Rα and inhibits signaling of both IL-4 and IL-13, has shown efficacy across multiple diseases with underlying type 2 signatures and is approved for treatment of asthma, atopic dermatitis, and chronic sinusitis with nasal polyposis. We sought to provide a comprehensive analysis of the redundant and distinct roles of IL-4 and IL-13 in type 2 inflammation and report dupilumab mechanisms of action. METHODS Using primary cell assays and a mouse model of house dust mite-induced asthma, we compared IL-4 vs IL-13 vs IL-4Rα blockers. RESULTS Intranasal administration of either IL-4 or IL-13 confers an asthma-like phenotype in mice by inducing immune cell lung infiltration, including eosinophils, increasing cytokine/chemokine expression and mucus production, thus demonstrating redundant functions of these cytokines. We further teased out their respective contributions using human in vitro culture systems. Then, in a mouse asthma model by comparing in head-to-head studies, either IL-4 or IL-13 inhibition to dual IL-4/IL-13 inhibition, we demonstrate that blockade of both IL-4 and IL-13 is required to broadly block type 2 inflammation, which translates to protection from allergen-induced lung function impairment. Notably, only dual IL-4/IL-13 blockade prevented eosinophil infiltration into lung tissue without affecting circulating eosinophils, demonstrating that tissue, but not circulating eosinophils, contributes to disease pathology. CONCLUSIONS Overall, these data support IL-4 and IL-13 as key drivers of type 2 inflammation and help provide insight into the therapeutic mechanism of dupilumab, a dual IL-4/IL-13 blocker, in multiple type 2 diseases.
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Affiliation(s)
| | | | | | | | | | | | - Yu Bai
- Regeneron Pharmaceuticals Tarrytown NY USA
| | | | | | | | | | - Jee H. Kim
- Regeneron Pharmaceuticals Tarrytown NY USA
| | | | | | - Neil Stahl
- Regeneron Pharmaceuticals Tarrytown NY USA
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Elliot JG, Noble PB, Mauad T, Bai TR, Abramson MJ, McKay KO, Green FH, James AL. Inflammation‐dependent and independent airway remodelling in asthma. Respirology 2018; 23:1138-1145. [PMID: 29943875 DOI: 10.1111/resp.13360] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2018] [Revised: 05/21/2018] [Accepted: 06/05/2018] [Indexed: 01/21/2023]
Affiliation(s)
- John G. Elliot
- West Australian Sleep Disorders Research Institute, Department of Pulmonary Physiology and Sleep MedicineSir Charles Gairdner Hospital Perth WA Australia
| | - Peter B. Noble
- School of Human SciencesUniversity of Western Australia Perth WA Australia
- Centre for Neonatal Research and Education, School of Paediatrics and Child HealthUniversity of Western Australia Perth WA Australia
| | - Thais Mauad
- Department of PathologyUniversity Medical School Sao Paulo Brazil
| | - Tony R. Bai
- Department of MedicineUniversity of British Columbia Vancouver BC Canada
| | - Michael J. Abramson
- Department of Epidemiology and Preventive MedicineMonash University Melbourne VIC Australia
| | - Karen O. McKay
- Department of Respiratory MedicineChildren's Hospital at Westmead Sydney NSW Australia
| | - Francis H.Y. Green
- Department of Pathology and Laboratory MedicineUniversity of Calgary Calgary AB Canada
| | - Alan L. James
- West Australian Sleep Disorders Research Institute, Department of Pulmonary Physiology and Sleep MedicineSir Charles Gairdner Hospital Perth WA Australia
- School of Medicine and PharmacologyUniversity of Western Australia Perth WA Australia
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Afrin LB. A new era for an old cell: heightened appreciation of mast cell disease emerges. Transl Res 2016; 174:1-4. [PMID: 27016701 DOI: 10.1016/j.trsl.2016.03.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2016] [Accepted: 03/03/2016] [Indexed: 02/06/2023]
Affiliation(s)
- Lawrence B Afrin
- Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, Minn.
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Mast cell activation disease and the modern epidemic of chronic inflammatory disease. Transl Res 2016; 174:33-59. [PMID: 26850903 DOI: 10.1016/j.trsl.2016.01.003] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2015] [Revised: 01/07/2016] [Accepted: 01/08/2016] [Indexed: 12/18/2022]
Abstract
A large and growing portion of the human population, especially in developed countries, suffers 1 or more chronic, often quite burdensome ailments which either are overtly inflammatory in nature or are suspected to be of inflammatory origin, but for which investigations to date have failed to identify specific causes, let alone unifying mechanisms underlying the multiple such ailments that often afflict such patients. Relatively recently described as a non-neoplastic cousin of the rare hematologic disease mastocytosis, mast cell (MC) activation syndrome-suspected to be of greatly heterogeneous, complex acquired clonality in many cases-is a potential underlying/unifying explanation for a diverse assortment of inflammatory ailments. A brief review of MC biology and how aberrant primary MC activation might lead to such a vast range of illness is presented.
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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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9
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Afrin LB, Molderings GJ. A concise, practical guide to diagnostic assessment for mast cell activation disease. World J Hematol 2014; 3:1-17. [DOI: 10.5315/wjh.v3.i1] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
As recognition of mast cell (MC) involvement in a range of chronic inflammatory disorders has increased, diagnosticians’ suspicions of MC activation disease (MCAD) in their chronically mysteriously inflamed patients have similarly increased. It is now understood that the various forms of systemic mastocytosis - diseases of inappropriate activation and proliferation of MCs seemingly driven by a small set of rare, usually constitutively activating mutations in assorted MC regulatory elements - comprise merely the tip of the MCAD iceberg, whereas the far larger and far more clinically heterogeneous (and thus more difficult to recognize) bulk of the iceberg consists of assorted forms of MC activation syndrome (MCAS) which manifest little to no abnormal MC proliferation and may originate from a far more heterogeneous set of MC mutations. It is reasonable to suspect MCAD when symptoms and signs of MC activation are present and no other diagnosis better accounting for the full range of findings is present. Initial laboratory assessment should include not only routine blood counts and serum chemistries but also a serum total tryptase level, which helps direct further evaluation for mastocytosis vs MCAS. Appropriate tissue examinations are needed to diagnose mastocytosis, while elevated levels of relatively specific mast cell mediators are sought to support diagnosis of MCAS. Whether assessing for mastocytosis or MCAS, testing is fraught with potential pitfalls which can easily yield false negatives leading to erroneous rejection of diagnostic consideration of MCAD in spite of a clinical history highly consistent with MCAD. Efforts at accurate diagnosis of MCAD are worthwhile, as many patients then respond well to appropriately directed therapeutic efforts.
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10
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Afrin LB, Molderings GJ. A concise, practical guide to diagnostic assessment for mast cell activation disease. World J Hematol 2014; 3:1-17. [DOI: 10.5315/wjh.v3.i1.1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
As recognition of mast cell (MC) involvement in a range of chronic inflammatory disorders has increased, diagnosticians’ suspicions of MC activation disease (MCAD) in their chronically mysteriously inflamed patients have similarly increased. It is now understood that the various forms of systemic mastocytosis - diseases of inappropriate activation and proliferation of MCs seemingly driven by a small set of rare, usually constitutively activating mutations in assorted MC regulatory elements - comprise merely the tip of the MCAD iceberg, whereas the far larger and far more clinically heterogeneous (and thus more difficult to recognize) bulk of the iceberg consists of assorted forms of MC activation syndrome (MCAS) which manifest little to no abnormal MC proliferation and may originate from a far more heterogeneous set of MC mutations. It is reasonable to suspect MCAD when symptoms and signs of MC activation are present and no other diagnosis better accounting for the full range of findings is present. Initial laboratory assessment should include not only routine blood counts and serum chemistries but also a serum total tryptase level, which helps direct further evaluation for mastocytosis vs MCAS. Appropriate tissue examinations are needed to diagnose mastocytosis, while elevated levels of relatively specific mast cell mediators are sought to support diagnosis of MCAS. Whether assessing for mastocytosis or MCAS, testing is fraught with potential pitfalls which can easily yield false negatives leading to erroneous rejection of diagnostic consideration of MCAD in spite of a clinical history highly consistent with MCAD. Efforts at accurate diagnosis of MCAD are worthwhile, as many patients then respond well to appropriately directed therapeutic efforts.
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11
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Ali H. Regulation of human mast cell and basophil function by anaphylatoxins C3a and C5a. Immunol Lett 2009; 128:36-45. [PMID: 19895849 DOI: 10.1016/j.imlet.2009.10.007] [Citation(s) in RCA: 88] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2009] [Revised: 10/21/2009] [Accepted: 10/23/2009] [Indexed: 12/18/2022]
Abstract
Allergic diseases such as asthma result from inappropriate immunologic responses to common environmental allergens in genetically susceptible individuals. Following allergen exposure, interaction of dendritic cells (DC) with CD4(+) T cells leads to the production of Th2 cytokines, which induce B cells to synthesize IgE molecules (sensitization phase). These IgE molecules bind to their high affinity receptors (FcvarepsilonRI) on the surface of mast cells and basophils and their subsequent cross-linking by allergen results in the release of preformed and newly synthesized mediators, which cause bronchoconstriction, lung inflammation and airway hyperresponsiveness (AHR) in asthma (effector phase). The complement components C3a and C5a levels are increased in the lungs of patients with asthma and are likely generated via the actions of both allergen and mast cell proteases. In vivo studies with rodents have shown that while C3a facilitates allergen sensitization in some models C5a inhibits this response. Despite this difference, both anaphylatoxins promote lung inflammation and AHR in vivo indicating that cells other than DC and T cells likely mediate the functional effects of C3a and C5a in asthma. This review focuses on the contribution of C3a and C5a in the pathogenesis of asthma with a particular emphasis on mast cells and basophils. It discusses the mechanisms by which anaphylatoxins activate mast cells and basophils and the associated signaling pathways via which their receptors are regulated by priming and desensitization.
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Affiliation(s)
- Hydar Ali
- Department of Pathology, University of Pennsylvania School of Dental Medicine, 240 South 40th Street, Philadelphia, PA 19104-6030, USA.
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12
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Bischoff SC. Physiological and pathophysiological functions of intestinal mast cells. Semin Immunopathol 2009; 31:185-205. [PMID: 19533134 DOI: 10.1007/s00281-009-0165-4] [Citation(s) in RCA: 158] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2009] [Accepted: 05/25/2009] [Indexed: 12/16/2022]
Abstract
The normal gastrointestinal (GI) mucosa is equipped with mast cells that account for 2-3% of lamina propria cells under normal conditions. Mast cells are generally associated with allergic disease, and indeed, food allergy that manifests in the GI tract is usually mast cell dependent. On the other hand, mast cells have a number of physiological functions in the GI tract, namely regulatory functions such as control of blood flow and coagulation, smooth muscle contraction and peristalsis, and secretion of acid, electrolytes, and mucus by epithelial cells. One of the most intriguing functions of intestinal mast cells is their role in host defense against microbes like bacteria, viruses, or parasites. Mast cells recognize microbes by antibody-dependent mechanisms and through pattern-recognition receptors. They direct the subsequent immune response by attracting both granulocytes and lymphocytes to the site of challenge via paracrine cytokine release. Moreover, mast cells initiate, by releasing proinflammatory mediators, innate defense mechanisms such as enhanced epithelial secretion, peristalsis, and alarm programs of the enteric nervous This initiation can occur in response to a primary contact to the microbe or other danger signals, but becomes much more effective if the triggering antigen reappears and antibodies of the IgE or IgG type have been generated in the meantime by the specific immune system. Thus, mast cells operate at the interface between innate and adaptive immune responses to enhance the defense against pathogens and, most likely, the commensal flora. In this respect, it is important to note that mast cells are directly involved in controlling the function of the intestinal barrier that turned out to be a crucial site for the development of infectious and immune-mediated diseases. Hence, intestinal mast cells perform regulatory functions to maintain tissue homeostasis, they are involved in host defense mechanisms against pathogens, and they can induce allergy once they are sensitized against foreign antigens. The broad spectrum of functions makes mast cells a fascinating target for future pharmacological or nutritional interventions.
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Affiliation(s)
- Stephan C Bischoff
- Department of Nutritional Medicine & Immunology, University of Hohenheim, Stuttgart, Germany.
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Headley MB, Zhou B, Shih WX, Aye T, Comeau MR, Ziegler SF. TSLP conditions the lung immune environment for the generation of pathogenic innate and antigen-specific adaptive immune responses. THE JOURNAL OF IMMUNOLOGY 2009; 182:1641-7. [PMID: 19155513 DOI: 10.4049/jimmunol.182.3.1641] [Citation(s) in RCA: 91] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Thymic stromal lymphopoietin (TSLP) is crucial for the development of atopic diseases in humans and mice. Mice that express a lung-specific TSLP transgene (surfactant protein C promoter (SPC)-TSLP) develop a spontaneous and progressive asthma-like disease, suggesting that TSLP expression alone was sufficient for disease development. In this study, we show that, in fact, TSLP alone only causes a weak innate response that is insufficient for development of full airway inflammatory disease. Complete disease development requires both TSLP and antigenic stimulation. These data suggest that the spontaneous lung inflammation observed in SPC-TSLP mice reflects a TSLP-driven predisposition toward the development of aberrant responses against innocuous environmental Ags. This provides evidence that TSLP may act directly to induce susceptibility to the inappropriate allergic responses that characterize atopy and asthma. We additionally show that disease development requires CD4 T cells but not B cells. Further, we reveal a TSLP-driven innate response involving mucus overproduction and goblet cell metaplasia. Taken together, these data suggest a multifaceted model of TSLP-mediated airway inflammation, with an initial activation of resident innate immune cells, followed by activation of the adaptive immune system and full disease development. This study provides new insight into the unique features of the asthma pathology contributed by the innate and adaptive immune responses in response to TSLP stimulation.
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Affiliation(s)
- Mark B Headley
- Department of Immunology, University of Washington School of Medicine, Seattle, WA 98195, USA
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Barnard R, Barnard A, Salmon G, Liu W, Sreckovic S. Histamine-induced actin polymerization in human eosinophils: an imaging approach for histamine H4 receptor. Cytometry A 2008; 73:299-304. [PMID: 18163465 DOI: 10.1002/cyto.a.20514] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
Image-based screening, a new and flexible tool in the drug discovery cascade, is amenable to many different targets. This article describes a particular use of the Cellomics ArrayScan in developing a functional screen for histamine H(4) receptor (H(4)R) antagonists that have potential utility in inflammatory diseases of the airways such as asthma, with H(4)R being expressed on a wide variety of immune cells including eosinophils. Exposure to histamine causes eosinophils to migrate from the bloodstream into the tissue where they contribute to inflammation. Migration is manifested through rearrangements of the actin cytoskeleton and phalloidin, a biological peptide, selectively binds F-actin over G-actin and can be used to detect these cytoskeletal changes mediating inflammatory function. A fluorescent conjugate of phalloidin was used to visualize histamine-induced actin polymerization in human eosinophils on the Cellomics ArrayScan. Inhibition of this phenomenon by commercially available histamine receptor antagonists was measured. The selective H(4)R antagonist JNJ7777120 inhibited histamine-induced actin polymerization in eosinophils most potently. This assay illustrates that this phenomenon is mediated through the H(4)R and that the image-based format has enhanced screening utility for identifying selective H(4)R antagonists over traditional flow cytometry methods.
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Affiliation(s)
- Ruth Barnard
- Biomarkers & Translational Biology, Pfizer, Sandwich, Kent, United Kingdom.
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15
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Brown JM, Wilson TM, Metcalfe DD. The mast cell and allergic diseases: role in pathogenesis and implications for therapy. Clin Exp Allergy 2007; 38:4-18. [PMID: 18031566 DOI: 10.1111/j.1365-2222.2007.02886.x] [Citation(s) in RCA: 126] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Mast cells have long been recognized for their role in the genesis of allergic inflammation; and more recently for their participation in innate and acquired immune responses. Mast cells reside within tissues including the skin and mucosal membranes, which interface with the external environment; as well as being found within vascularized tissues next to nerves, blood vessels and glandular structures. Mast cells have the capability of reacting both within minutes and over hours to specific stimuli, with local and systemic effects. Mast cells express the high affinity IgE receptor (FcepsilonRI) and upon aggregation of FcepsilonRI by allergen-specific IgE, mast cells release and generate biologically active preformed and newly synthesized mediators which are involved in many aspects of allergic inflammation. While mast cells have been well documented to be essential for acute allergic reactions, more recently the importance of mast cells in reacting through pattern recognition receptors in innate immune responses has become recognized. Moreover, as our molecular understanding of the mast cell has evolved, novel targets for modulation have been identified with promising therapeutic potential.
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Affiliation(s)
- J M Brown
- Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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16
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Zaidi AK, Ali H. C3a receptors signaling in mast cells. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2007; 598:126-40. [PMID: 17892209 DOI: 10.1007/978-0-387-71767-8_10] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Affiliation(s)
- Asifa K Zaidi
- University of Pennsylvania School of Dental Medicine, Department of Pathology, Philadelphia, PA 19104, USA.
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17
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Kaur D, Hollins F, Woodman L, Yang W, Monk P, May R, Bradding P, Brightling CE. Mast cells express IL-13R alpha 1: IL-13 promotes human lung mast cell proliferation and Fc epsilon RI expression. Allergy 2006; 61:1047-53. [PMID: 16918506 DOI: 10.1111/j.1398-9995.2006.01139.x] [Citation(s) in RCA: 68] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
BACKGROUND The Th2 cytokine interleukin (IL)-13 is implicated in the development of various allergic diseases including asthma. The IL-13 receptor, IL-13Ralpha1, is expressed on most leukocytes, except T-cells. Evidence to support IL-13Ralpha1 expression on mast cells is limited. METHODS We investigated: (i) IL-13Ralpha1 expression by human lung mast cells (HLMC); (ii) the number of IL-13Ralpha1+ bronchial submucosal mast cells in subjects with asthma and normal controls and (iii) the effect of IL-13 priming on HLMC expression of high-affinity IgE receptor (FcepsilonRI), stem cell factor receptor (CD117), histamine release, proliferation, and survival. RESULTS Human lung mast cell expressed IL-13Ralpha1 mRNA. IL-13Ralpha1 was highly expressed on the surface HLMC (82+/-9%). Bronchial submucosal mast cell IL-13Ralpha1 expression was higher in asthmatics (86+/-2%) than normal controls (78+/-2%; P=0.015). IL-13 priming for 30 min did not increase HLMC histamine release, in the presence or absence of SCF or in response to IgE/anti-IgE activation. IL-13 priming for 5 days upregulated HLMC FcepsilonRI expression (22% increase in fluorescent intensity; P=0.003), increased histamine release following IgE/anti-IgE activation by 56% (P=0.03) and increased proliferation by 50% (P=0.003) without affecting cell survival or CD117 expression. The IL-13 specific neutralizing antibody CAT-354 inhibited all IL-13 mediated effects. CONCLUSION Human lung mast cell express IL-13Ralpha1 and activation by IL-13 for 5 days increased FcepsilonRI expression and proliferation. Histamine release was not affected by short-term priming with IL-13, but was upregulated by priming for 5 days suggesting that this effect was mediated by the increased FcepsilonRI expression. These data support the view that targeting IL-13 may be beneficial in the treatment of asthma.
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Affiliation(s)
- D Kaur
- Department of Infection, Institute for Lung Health, Inflammation and Immunity, University of Leicester, Leicester, UK
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18
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Dunford PJ, O'Donnell N, Riley JP, Williams KN, Karlsson L, Thurmond RL. The histamine H4 receptor mediates allergic airway inflammation by regulating the activation of CD4+ T cells. THE JOURNAL OF IMMUNOLOGY 2006; 176:7062-70. [PMID: 16709868 DOI: 10.4049/jimmunol.176.11.7062] [Citation(s) in RCA: 205] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Histamine is an important inflammatory mediator that is released in airways during an asthmatic response. However, current antihistamine drugs are not effective in controlling the disease. The discovery of the histamine H4 receptor (H4R) prompted us to reinvestigate the role of histamine in pulmonary allergic responses. H4R-deficient mice and mice treated with H4R antagonists exhibited decreased allergic lung inflammation, with decreases in infiltrating lung eosinophils and lymphocytes and decreases in Th2 responses. Ex vivo restimulation of T cells showed decreases in IL-4, IL-5, IL-13, IL-6, and IL-17 levels, suggesting that T cell functions were disrupted. In vitro studies indicated that blockade of the H4R on dendritic cells leads to decreases in cytokine and chemokine production and limits their ability to induce Th2 responses in T cells. This work suggests that the H4R can modulate allergic responses via its influence on T cell activation. The study expands the known influences of histamine on the immune system and highlights the therapeutic potential of H4R antagonists in allergic conditions.
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MESH Headings
- Allergens/administration & dosage
- Animals
- Benzimidazoles/administration & dosage
- CD4-Positive T-Lymphocytes/cytology
- CD4-Positive T-Lymphocytes/immunology
- CD4-Positive T-Lymphocytes/metabolism
- Cells, Cultured
- Cytokines/antagonists & inhibitors
- Cytokines/biosynthesis
- Disease Models, Animal
- Female
- Indoles/administration & dosage
- Inflammation/immunology
- Inflammation/metabolism
- Lung/immunology
- Lung/pathology
- Lymphocyte Activation/immunology
- Mice
- Mice, Inbred BALB C
- Mice, Knockout
- Mice, Mutant Strains
- Mice, Transgenic
- Ovalbumin/administration & dosage
- Piperazines/administration & dosage
- Receptors, G-Protein-Coupled/antagonists & inhibitors
- Receptors, G-Protein-Coupled/deficiency
- Receptors, G-Protein-Coupled/genetics
- Receptors, G-Protein-Coupled/physiology
- Receptors, Histamine/deficiency
- Receptors, Histamine/genetics
- Receptors, Histamine/physiology
- Receptors, Histamine H4
- Respiratory Hypersensitivity/genetics
- Respiratory Hypersensitivity/immunology
- Respiratory Hypersensitivity/metabolism
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Affiliation(s)
- Paul J Dunford
- Johnson & Johnson Pharmaceutical Research and Development, San Diego, CA 92121, USA
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Sim ATR, Ludowyke RI, Verrills NM. Mast cell function: regulation of degranulation by serine/threonine phosphatases. Pharmacol Ther 2006; 112:425-39. [PMID: 16790278 DOI: 10.1016/j.pharmthera.2006.04.011] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2006] [Accepted: 04/26/2006] [Indexed: 01/28/2023]
Abstract
Mast cells play both effector and modulatory roles in a range of allergic and immune responses. The principal function of these cells is the release of inflammatory mediators from mast cells by degranulation, which involves a complex interplay of signalling molecules. Understanding the molecular architecture underlying mast cell signalling has attracted renewed interest as the capacity for therapeutic intervention through controlling mast cell degranulation is now accepted as a viable proposition. The dynamic regulation of signalling by protein phosphorylation is a well-established phenomenon and many of the early events involved in mast cell activation are well understood. Less well understood however are the events further downstream of receptor activation that allow movement of granules through the cytoskeletal barrier and docking and fusion of granules with the plasma membrane. Whilst a potential role for the protein phosphatase family of signalling enzymes in mast cell function has been accepted for some time, the evidence has largely been derived from the use of broad specificity pharmacological inhibitors and results often depend upon the experimental conditions, leading to conflicting views. In this review, we present and discuss the pharmacological and recent molecular evidence that protein phosphatases, and in particular the protein phosphatase serine/threonine phosphatase type 2A (PP2A), have major regulatory roles to play and may be potential targets for the design of new therapeutic agents.
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Affiliation(s)
- Alistair T R Sim
- School of Biomedical Sciences and Hunter Medical Research Institute, Faculty of Health, The University of Newcastle, Callaghan, NSW, Australia.
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Abstract
Inflammation is an important manifestation of respiratory disease in domestic animals. The respiratory system is mucosal in nature and has specific defense mechanisms used to control invasion by microbes and environmental elements. Inflammation can be beneficial or detrimental to the host. This article broadly discusses the primary mediators and mechanisms of inflammation within the respiratory tract of domestic animals. The role of cells, chemokines, cytokines and mediators in both acute and chronic inflammation are addressed. The pathogenesis of the initial insult determines the type of inflammation that will be induced, whether it is acute, chronic or allergic in origin. Maintenance of the microenvironment of cytokines and chemokines is critical for pulmonary homeostasis. Uncontrolled inflammation in the respiratory tract can be life threatening to the animal. The understanding of the mechanisms of inflammation, whether due to microbes or through inappropriate immune activation such as those occurring with allergies, is required to develop successful intervention strategies and control respiratory disease in animals.
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Affiliation(s)
- Eileen L Thacker
- Department of Veterinary Microbiology and Preventive Medicine, College of Veterinary Medicine, Iowa State University, Ames, 50011, USA.
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Lino dos Santos Franco A, Damazo AS, Beraldo de Souza HR, Domingos HV, Oliveira-Filho RM, Oliani SM, Costa SKP, Tavares de Lima W. Pulmonary neutrophil recruitment and bronchial reactivity in formaldehyde-exposed rats are modulated by mast cells and differentially by neuropeptides and nitric oxide. Toxicol Appl Pharmacol 2006; 214:35-42. [PMID: 16427670 DOI: 10.1016/j.taap.2005.11.014] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2005] [Revised: 11/25/2005] [Accepted: 11/28/2005] [Indexed: 10/25/2022]
Abstract
We have used a pharmacological approach to study the mechanisms underlying the rat lung injury and the airway reactivity changes induced by inhalation of formaldehyde (FA) (1% formalin solution, 90 min once a day, 4 days). The reactivity of isolated tracheae and intrapulmonary bronchi were assessed in dose-response curves to methacholine (MCh). Local and systemic inflammatory phenomena were evaluated in terms of leukocyte countings in bronchoalveolar lavage (BAL) fluid, blood, bone marrow lavage and spleen. Whereas the tracheal reactivity to MCh did not change, a significant bronchial hyporesponsiveness (BHR) was found after FA inhalation as compared with naive rats. Also, FA exposure significantly increased the total cell numbers in BAL, in peripheral blood and in the spleen, but did not modify the counts in bone marrow. Capsaicin hindered the increase of leukocyte number recovered in BAL fluid after FA exposure. Both compound 48/80 and indomethacin were able to prevent the lung neutrophil influx after FA, but indomethacin had no effect on that of mononuclear cells. Following FA inhalation, the treatment with sodium cromoglycate (SCG), but not with the nitric oxide (NO) synthase inhibitor L-NAME, significantly reduced the total cell number in BAL. Compound 48/80, L-NAME and SCG significantly prevented BHR to MCh after FA inhalation, whereas capsaicin was inactive in this regard. On the other hand, indomethacin exacerbated BHR. These data suggest that after FA inhalation, the resulting lung leukocyte influx and BHR may involve nitric oxide, airway sensory fibers and mast cell-derived mediators. The effect of NO seemed to be largely restricted to the bronchial tonus, whereas neuropeptides appeared to be linked to the inflammatory response, therefore indicating that the mechanisms responsible for the changes of airway responsiveness caused by FA may be separate from those underlying its inflammatory lung effects.
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