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Joulia R, Patti S, Traves WJ, Loewenthal L, Yates L, Walker SA, Puttur F, Al-Sahaf M, Cahill KN, Lai J, Siddiqui S, Boyce JA, Israel E, Lloyd CM. A single-cell spatial chart of the airway wall reveals proinflammatory cellular ecosystems and their interactions in health and asthma. Nat Immunol 2025:10.1038/s41590-025-02161-3. [PMID: 40399607 DOI: 10.1038/s41590-025-02161-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Accepted: 04/11/2025] [Indexed: 05/23/2025]
Abstract
Determining spatial location of cells within tissues gives vital insight into the interactions between resident and inflammatory cells and is a critical factor for uncoupling the mechanisms driving disease. Here, we apply single-cell spatial transcriptomics to reveal the airway wall landscape in health and during asthma. We identified proinflammatory cellular ecosystems that exist within discrete spatial niches in healthy and asthma samples. These cellular hubs are characterized by a high level of chemokine and alarmin expression, along with unique combinations of stromal cells. Mechanistically, we demonstrated that receptors, such as ACKR1, retain immune mediators locally, while amphiregulin-expressing mast cells are prominent within these proinflammatory hubs. Despite anti-inflammatory treatments, the asthma airway mucosa exhibited a distinct remodeling program within these cellular ecosystems, marked by increased proximity between key cell types. This study provides an unprecedented view of the topography of the airway wall, revealing distinct, specific ecosystems within spatial niches to target for therapeutic intervention.
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Affiliation(s)
- Régis Joulia
- National Heart and Lung Institute, Imperial College London, London, UK.
| | - Sara Patti
- National Heart and Lung Institute, Imperial College London, London, UK
| | - William J Traves
- National Heart and Lung Institute, Imperial College London, London, UK
| | - Lola Loewenthal
- National Heart and Lung Institute, Imperial College London, London, UK
- Department of Asthma and Allergy, Royal Brompton and Harefield Hospitals, London, UK
- Department of Respiratory Medicine, Royal Brompton and Harefield Hospitals, London, UK
| | - Laura Yates
- National Heart and Lung Institute, Imperial College London, London, UK
| | - Simone A Walker
- National Heart and Lung Institute, Imperial College London, London, UK
| | - Franz Puttur
- National Heart and Lung Institute, Imperial College London, London, UK
| | - May Al-Sahaf
- National Heart and Lung Institute, Imperial College London, London, UK
| | - Katherine N Cahill
- Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Juying Lai
- Departments of Medicine and Pediatrics, Harvard Medical School, Boston, MA, USA
- Jeff and Penny Vinik Center for Allergic Disease Research, Division of Allergy and Clinical Immunology, Brigham and Women's Hospital, Boston, MA, USA
| | - Salman Siddiqui
- National Heart and Lung Institute, Imperial College London, London, UK
- Department of Respiratory Sciences, University of Leicester, Leicester, UK
| | - Joshua A Boyce
- Departments of Medicine and Pediatrics, Harvard Medical School, Boston, MA, USA
- Jeff and Penny Vinik Center for Allergic Disease Research, Division of Allergy and Clinical Immunology, Brigham and Women's Hospital, Boston, MA, USA
| | - Elliot Israel
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
| | - Clare M Lloyd
- National Heart and Lung Institute, Imperial College London, London, UK.
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Zeng H, Zhang H, Liu Z, Liu J, Xie B, Zeng L, Wang X, Shu Q, Tang P, Mo L, Zhao M, Yang P. Dynactin Subunit 1 Facilitates Mast Cell Degranulation to Drive Food Allergy Pathogenesis. Immunol Lett 2025:107035. [PMID: 40404107 DOI: 10.1016/j.imlet.2025.107035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Revised: 05/14/2025] [Accepted: 05/19/2025] [Indexed: 05/24/2025]
Abstract
BACKGROUND Mast cells play pivotal roles in allergic pathogenesis and inflammatory disorders, with their pathologic effects largely mediated through granule exocytosis. Dynactin subunit 1 (Dctn1), a microtubule-associated motor protein, remains unexplored in mast cell-driven inflammation. This study investigates Dctn1's functional role in regulating mast cell degranulation during food allergy (FA). METHODS An ovalbumin-sensitized murine FA model was established to profile mast cell activity. Gut lavage fluid (GLF) was analyzed via Olink proteomics and ELISA to quantify Dctn1 levels and mast cell mediators (histamine, Mcpt1). Mechanistic studies employed RNA interference, conditional knockout mice (Dctn1f/fCma1-Cre), and immunoprecipitation to assess Dctn1's role in granule trafficking. RESULTS FA mice exhibited 3.2-fold higher Dctn1 levels in GLF versus controls (p < 0.001), strongly correlating with mast cell mediator concentrations (histamine: r = 0.73; Mcpt1: r = 0.7). Intestinal mast cells showed selective Dctn1 upregulation (2.8-fold mRNA increase, p < 0.01), mechanistically linked to granule trafficking through CMA1 complex formation. Mast cell-specific Dctn1 ablation reduced Mcpt1 release by 74% (p < 0.001) and ameliorated FA symptoms (92% core temperature drop, p < 0.005), independent of AKT/ERK signaling pathways. CONCLUSIONS This study identifies Dctn1 as a novel regulator of mast cell degranulation in FA, operating through microtubule-dependent granule transport. Targeted inhibition of Dctn1 significantly attenuates allergic responses without disrupting canonical activation signals, positioning it as a promising therapeutic target for mast cell-driven pathologies.
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Affiliation(s)
- Haotao Zeng
- Department of Otolaryngology, Longgang ENT Hospital & Shenzhen ENT Institute, Shenzhen, China
| | - Hanqing Zhang
- State Key Laboratory of Respiratory Disease Allergy Division at Shenzhen University and Institute of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen, China
| | - Zhiqiang Liu
- Department of Otolaryngology, Longgang ENT Hospital & Shenzhen ENT Institute, Shenzhen, China
| | - Jiangqi Liu
- Department of Otolaryngology, Longgang ENT Hospital & Shenzhen ENT Institute, Shenzhen, China
| | - Bailing Xie
- State Key Laboratory of Respiratory Disease Allergy Division at Shenzhen University and Institute of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen, China
| | - Lu Zeng
- State Key Laboratory of Respiratory Disease Allergy Division at Shenzhen University and Institute of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen, China
| | - Xiangyu Wang
- Department of Gastroenterology. Shenzhen People's Second Hospital. Shenzhen, China
| | - Qing Shu
- Department of Gastroenterology. Shenzhen People's Second Hospital. Shenzhen, China
| | - Ping Tang
- Department of General Practice Medicine, Third Affiliated Hospital of Shenzhen University, Shenzhen, China
| | - Lihua Mo
- Department of General Practice Medicine, Third Affiliated Hospital of Shenzhen University, Shenzhen, China
| | - Miao Zhao
- Department of Otolaryngology, Longgang ENT Hospital & Shenzhen ENT Institute, Shenzhen, China.
| | - Pingchang Yang
- State Key Laboratory of Respiratory Disease Allergy Division at Shenzhen University and Institute of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen, China.
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Zhang Y, Peng G, Zhang R. Taraxasterol attenuates inflammatory responses in a 2,4-dinitrochlorobenzene-induced atopic dermatitis mouse model via inactivation of the MAPK and NF-κB pathways. J Mol Histol 2025; 56:115. [PMID: 40119084 DOI: 10.1007/s10735-025-10391-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2025] [Accepted: 03/06/2025] [Indexed: 03/24/2025]
Abstract
Atopic dermatitis (AD) is an inflammatory skin disease. Taraxasterol has anti-inflammatory effects in various pathological processes. In this study, our goal is to detect the biological functions of taraxasterol and its related mechanisms in AD development. The mouse model of experimental AD was established through application of 2',4-dintrochlorobenzene (DNCB) onto the mouse dorsal skin. Taraxasterol (2.5, 5, and 10 mg/kg) was orally administrated to AD mice. Effects of taraxasterol on AD-like skin symptoms were examined through assessment of ratios of skin lesion area/dorsal skin region, skin thickness, skin hydration, and starching number. Histopathological changes were detected by performing H&E staining. ELISA kits were obtained to measure serum TNF-α and IgE levels. RT-qPCR was conducted to measure mRNA levels of proinflammatory factors. Expression of MAPKs and NF-κB signaling was evaluated by western blotting. Taraxasterol alleviated AD-like skin symptoms (erosions, erythema, scaling, dryness, pruritus) and reduced lesion area and skin thickness in mice with DNCB-induced AD. Taraxasterol decreased epidermal thickness and serum levels of IgE and TNF-α and prevented the release of proinflammatory factors in lesion sites in of DNCB-induced AD mice. Mechanistically, taraxasterol inactivated the MAPK and NF-κB pathways. Taraxasterol alleviates AD-like skin symptoms and inflammation in a DNCB-induced AD mouse model via inactivation of the MAPK and NF-κB pathways.
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Affiliation(s)
- Yu Zhang
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, Jiangsu, China
| | - Guoping Peng
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, Jiangsu, China
| | - Rusheng Zhang
- Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, #155 Hanzhong Road, Qinhuai District, Nanjing, 210029, China.
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Choi MY, Jo MG, Min KY, Kim B, Kim Y, Choi WS. Antimicrobial Peptide Pro10-1D Exhibits Anti-Allergic Activity: A Promising Therapeutic Candidate. Int J Mol Sci 2024; 25:12138. [PMID: 39596204 PMCID: PMC11594534 DOI: 10.3390/ijms252212138] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 11/08/2024] [Accepted: 11/11/2024] [Indexed: 11/28/2024] Open
Abstract
Although antimicrobial peptides (AMPs) exhibit a range of biological functions, reports on AMPs with therapeutic effects in allergic disorders are limited. In this study, we investigated the anti-allergic effects of Pro10-1D, a 10-meric AMP derived from insect defensin protaetiamycine. Our findings demonstrate that Pro10-1D effectively inhibits antigen-induced degranulation of mast cells (MCs) with IC50 values of approximately 11.6 μM for RBL-2H3 cells and 2.7 μM for bone marrow-derived MCs. Furthermore, Pro10-1D suppressed the secretion of cytokines with IC50 values of approximately 2.8 μM for IL-4 and approximately 8.6 μM for TNF-α. Mechanistically, Pro10-1D inhibited the Syk-LAT-PLCγ1 signaling pathway in MCs and decreased the activation of mitogen-activated protein kinases (MAPKs). Pro10-1D demonstrated a dose-dependent reduction in IgE-mediated passive cutaneous anaphylaxis in mice with an ED50 value of approximately 7.6 mg/kg. Further investigation revealed that Pro10-1D significantly reduced the activity of key kinases Fyn and Lyn, which are critical in the initial phase of the FcεRI-mediated signaling pathway, with IC50 values of approximately 22.6 μM for Fyn and approximately 1.5 μM for Lyn. Collectively, these findings suggest that Pro10-1D represents a novel therapeutic candidate for the treatment of IgE-mediated allergic disorders by targeting the Lyn/Fyn Src family kinases in MCs.
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Affiliation(s)
- Min Yeong Choi
- Department of Immunology, College of Medicine, Konkuk University, Chungju 27478, Republic of Korea
| | - Min Geun Jo
- Department of Immunology, College of Medicine, Konkuk University, Chungju 27478, Republic of Korea
| | - Keun Young Min
- Department of Immunology, College of Medicine, Konkuk University, Chungju 27478, Republic of Korea
| | - Byeongkwon Kim
- Department of Bioscience and Biotechnology, Konkuk University, Seoul 05029, Republic of Korea
| | - Yangmee Kim
- Department of Bioscience and Biotechnology, Konkuk University, Seoul 05029, Republic of Korea
| | - Wahn Soo Choi
- Department of Immunology, College of Medicine, Konkuk University, Chungju 27478, Republic of Korea
- Institute of Biomedical Sciences & Technology, Konkuk University, Seoul 05029, Republic of Korea
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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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Feng L, Chen G, Guo Z, Yao W, Li X, Mu G, Zhu X. Both live and heat killed Lactiplantibacillus plantarum DPUL-F232 alleviate whey protein-induced food allergy by regulating cellular immunity and repairing the intestinal barrier. Food Funct 2024; 15:5496-5509. [PMID: 38690869 DOI: 10.1039/d4fo00105b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/03/2024]
Abstract
Postbiotics have been proposed as clinically viable alternatives to probiotics, addressing limitations and safety concerns associated with probiotic use. However, direct comparisons between the functional differences and health benefits of probiotics and postbiotics remain scarce. This study compared directly the desensitization effect of probiotics and postbiotics derived from Lactiplantibacillus plantarum strain DPUL-F232 in the whey protein-induced allergic rat model. The results demonstrate that administering both live and heat killed F232 significantly alleviated allergy symptoms, reduced intestinal inflammation, and decreased serum antibody and histamine levels in rats. Both forms of F232 were effective in regulating the Th1/Th2 balance, promoting the secretion of the regulatory cytokine IL-10, inhibiting mast cell degranulation and restoring the integrity of the intestinal barrier through the upregulation of tight junction proteins. Considering the enhanced stability and reduced safety concerns of postbiotics compared to probiotics, alongside their ability to regulate allergic reactions, we suggest that postbiotics may serve as viable substitutes for probiotics in managing food allergies and potentially other diseases.
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Affiliation(s)
- Lu Feng
- School of Food Science and Technology, Dalian Polytechnic University, Dalian, Liaoning, 116034, P. R. China.
- SKL of Marine Food Processing & Safety Control, National Engineering Research Center of Seafood, Dalian, Liaoning, 116034, P. R. China
| | - Gangliang Chen
- Xinjiang Wangyuan Camel Milk Industrial Co., Ltd, Fuhai, Xinjiang, 836400, P. R. China
| | - Zihao Guo
- School of Food Science and Technology, Dalian Polytechnic University, Dalian, Liaoning, 116034, P. R. China.
- SKL of Marine Food Processing & Safety Control, National Engineering Research Center of Seafood, Dalian, Liaoning, 116034, P. R. China
| | - Wenpu Yao
- School of Food Science and Technology, Dalian Polytechnic University, Dalian, Liaoning, 116034, P. R. China.
- SKL of Marine Food Processing & Safety Control, National Engineering Research Center of Seafood, Dalian, Liaoning, 116034, P. R. China
| | - Xinling Li
- Urumqi Dairy Industry Association, Urumqi, Xinjiang, 830000, P. R. China
| | - Guangqing Mu
- School of Food Science and Technology, Dalian Polytechnic University, Dalian, Liaoning, 116034, P. R. China.
- SKL of Marine Food Processing & Safety Control, National Engineering Research Center of Seafood, Dalian, Liaoning, 116034, P. R. China
| | - Xuemei Zhu
- School of Food Science and Technology, Dalian Polytechnic University, Dalian, Liaoning, 116034, P. R. China.
- SKL of Marine Food Processing & Safety Control, National Engineering Research Center of Seafood, Dalian, Liaoning, 116034, P. R. China
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Chang JH, Chuang HC, Fan CK, Hou TY, Chang YC, Lee YL. Norisoboldine exerts antiallergic effects on IgE/ovalbumin-induced allergic asthma and attenuates FcεRI-mediated mast cell activation. Int Immunopharmacol 2023; 121:110473. [PMID: 37331292 DOI: 10.1016/j.intimp.2023.110473] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 05/31/2023] [Accepted: 06/07/2023] [Indexed: 06/20/2023]
Abstract
Allergic asthma is an inflammatory lung disorder, and mast cells play crucial roles in the development of this allergic disease. Norisoboldine (NOR), the major isoquinoline alkaloid present in Radix Linderae, has received considerable attention because it has anti-inflammatory effects. Herein, the aim of this study was to explore the antiallergic effects of NOR on allergic asthma in mice and mast cell activation. In a murine model of ovalbumin (OVA)-induced allergic asthma, oral administration at 5 mg/kg body weight (BW) of NOR produced strong reductions in serum OVA-specific immunoglobulin E (IgE) levels, airway hyperresponsiveness, and bronchoalveolar lavage fluid (BALF) eosinophilia, while an increase in CD4+Foxp3+ T cells of the spleen was detected. Histological studies demonstrated that NOR treatment significantly ameliorated the progression of airway inflammation including the recruitment of inflammatory cells and mucus production by decreasing levels of histamine, prostaglandin D2 (PGD2), interleukin (IL)-4, IL-5, IL-6, and IL-13 in BALF. Furthermore, our results revealed that NOR (3 ∼ 30 μM) dose-dependently reduced expression of the high-affinity receptor for IgE (FcεRI) and the production of PGD2 and inflammatory cytokines (IL-4, IL-6, IL-13, and TNF-α), and also decreased degranulation of bone marrow-derived mast cells (BMMCs) activated by IgE/OVA. In addition, a similar suppressive effect on BMMC activation was observed by inhibition of the FcεRI-mediated c-Jun N-terminal kinase (JNK) signaling pathway using SP600125, a selective JNK inhibitor. Collectively, these results suggest that NOR may have therapeutic potential for allergic asthma at least in part through regulating the degranulation and the release of mediators by mast cells.
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Affiliation(s)
- Jer-Hwa Chang
- School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan; Division of Pulmonary Medicine, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Pulmonary Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
| | - Hsiao-Chi Chuang
- School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan; Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan; Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
| | - Chia-Kwung Fan
- Department of Molecular Parasitology and Tropical Diseases, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Tsung-Yun Hou
- Division of Rheumatology, Immunology and Allergy, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; Division of Allergy, Immunology and Rheumatology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Division of Rheumatology, Immunology and Allergy, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Yu-Cheng Chang
- Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Yueh-Lun Lee
- Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
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Spahn JD, Brightling CE, O’Byrne PM, Simpson LJ, Molfino NA, Ambrose CS, Martin N, Hallstrand TS. Effect of Biologic Therapies on Airway Hyperresponsiveness and Allergic Response: A Systematic Literature Review. J Asthma Allergy 2023; 16:755-774. [PMID: 37496824 PMCID: PMC10368134 DOI: 10.2147/jaa.s410592] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Accepted: 06/28/2023] [Indexed: 07/28/2023] Open
Abstract
Background Airway hyperresponsiveness (AHR) is a key feature of asthma. Biologic therapies used to treat asthma target specific components of the inflammatory pathway, and their effects on AHR can provide valuable information about the underlying disease pathophysiology. This review summarizes the available evidence regarding the effects of biologics on allergen-specific and non-allergen-specific airway responses in patients with asthma. Methods We conducted a systematic review in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, including risk-of-bias assessment. PubMed and Ovid were searched for studies published between January 1997 and December 2021. Eligible studies were randomized, placebo-controlled trials that assessed the effects of biologics on AHR, early allergic response (EAR) and/or late allergic response (LAR) in patients with asthma. Results Thirty studies were identified for inclusion. Bronchoprovocation testing was allergen-specific in 18 studies and non-allergen-specific in 12 studies. Omalizumab reduced AHR to methacholine, acetylcholine or adenosine monophosphate (3/9 studies), and reduced EAR (4/5 studies) and LAR (2/3 studies). Mepolizumab had no effect on AHR (3/3 studies), EAR or LAR (1/1 study). Tezepelumab reduced AHR to methacholine or mannitol (3/3 studies), and reduced EAR and LAR (1/1 study). Pitrakinra reduced LAR, with no effect on AHR (1/1 study). Etanercept reduced AHR to methacholine (1/2 studies). No effects were observed for lebrikizumab, tocilizumab, efalizumab, IMA-638 and anti-OX40 ligand on AHR, EAR or LAR; benralizumab on LAR; tralokinumab on AHR; and Ro-24-7472 on AHR or LAR (all 1/1 study each). No dupilumab or reslizumab studies were identified. Conclusion Omalizumab and tezepelumab reduced EAR and LAR to allergens. Tezepelumab consistently reduced AHR to methacholine or mannitol. These findings provide insights into AHR mechanisms and the precise effects of asthma biologics. Furthermore, findings suggest that tezepelumab broadly targets allergen-specific and non-allergic forms of AHR, and the underlying cells and mediators involved in asthma.
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Affiliation(s)
- Joseph D Spahn
- Respiratory and Immunology, BioPharmaceuticals Medical, AstraZeneca, Wilmington, DE, USA
| | - Christopher E Brightling
- Institute for Lung Health, NIHR Leicester Biomedical Research Centre, Department of Respiratory Sciences, University of Leicester, Leicester, UK
| | - Paul M O’Byrne
- Firestone Institute for Respiratory Health, St Joseph’s Hospital and Department of Medicine, McMaster University, Hamilton, Ontario, Canada
| | | | | | - Christopher S Ambrose
- Respiratory and Immunology, BioPharmaceuticals Medical, AstraZeneca, Gaithersburg, MD, USA
| | - Neil Martin
- Institute for Lung Health, NIHR Leicester Biomedical Research Centre, Department of Respiratory Sciences, University of Leicester, Leicester, UK
- Respiratory and Immunology, BioPharmaceuticals Medical, AstraZeneca, Cambridge, UK
| | - Teal S Hallstrand
- Division of Pulmonary, Critical Care and Sleep Medicine, and the Center for Lung Biology, Department of Medicine, University of Washington, Seattle, WA, USA
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9
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Wójcik-Pszczoła K, Pociecha K, Chłoń-Rzepa G, Zadrożna M, Nowak B, Plutecka H, Koczurkiewicz-Adamczyk P, Przejczowska-Pomierny K, Pękala E, Gosens R, Wyska E. Inhaled pan-phosphodiesterase inhibitors ameliorate ovalbumin-induced airway inflammation and remodeling in murine model of allergic asthma. Int Immunopharmacol 2023; 119:110264. [PMID: 37159965 DOI: 10.1016/j.intimp.2023.110264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 04/17/2023] [Accepted: 04/28/2023] [Indexed: 05/11/2023]
Abstract
Asthma is a heterogeneous, chronic respiratory disease characterized by airway inflammation and remodeling. Phosphodiesterase (PDE) inhibitors represent one of the intensively studied groups of potential anti-asthmatic agents due to their affecting both airway inflammation and remodeling. However, the effect of inhaled pan-PDE inhibitors on allergen induced asthma has not been reported to date. In this study we investigated the impact of two, representative strong pan-PDE inhibitors from the group of 7,8-disubstituted derivatives of 1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione: compound 38 and 145, on airway inflammation and remodeling in murine model of ovalbumin (OVA)-challenged allergic asthma. Female Balb/c mice were sensitized and challenged with OVA, 38 and 145 were administrated by inhalation, before each OVA challenge. The inhaled pan-PDE inhibitors markedly reduced the OVA-induced airway inflammatory cell infiltration, eosinophil recruitment, Th2 cytokine level in bronchoalveolar lavage fluid, as well as both, total and OVA-specific IgE levels in plasma. In addition, inhaled 38 and 145 decreased many typical features of airway remodeling, including goblet cell metaplasia, mucus hypersecretion, collagen overproduction and deposition, as well as Tgfb1, VEGF, and α-SMA expression in airways of allergen challenged mice. We also demonstrated that both 38 and 145 alleviate airway inflammation and remodelling by inhibition of the TGF-β/Smad signaling pathway activated in OVA-challenged mice. Taken together, these results suggest that the investigated pan-PDE inhibitors administered by inhalation are dual acting agents targeting both airway inflammation and remodeling in OVA-challenged allergic asthma and may represent promising, anti-asthmatic drug candidates.
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Affiliation(s)
- Katarzyna Wójcik-Pszczoła
- Jagiellonian University Medical College, Faculty of Pharmacy, Department of Pharmaceutical Biochemistry, Medyczna 9, 30-688 Kraków, Poland.
| | - Krzysztof Pociecha
- Jagiellonian University Medical College, Faculty of Pharmacy, Department of Pharmacokinetics and Physical Pharmacy, Medyczna 9, 30-688 Kraków, Poland
| | - Grażyna Chłoń-Rzepa
- Jagiellonian University Medical College, Faculty of Pharmacy, Department of Medicinal Chemistry, Medyczna 9, 30-688 Kraków, Poland
| | - Monika Zadrożna
- Jagiellonian University Medical College, Faculty of Pharmacy, Department of Cytobiology, Medyczna 9, 30-688 Kraków, Poland
| | - Barbara Nowak
- Jagiellonian University Medical College, Faculty of Pharmacy, Department of Cytobiology, Medyczna 9, 30-688 Kraków, Poland
| | - Hanna Plutecka
- Jagiellonian University Medical College, Faculty of Medicine, Department of Internal Medicine, Skawińska 8, 31-066 Kraków, Poland
| | - Paulina Koczurkiewicz-Adamczyk
- Jagiellonian University Medical College, Faculty of Pharmacy, Department of Pharmaceutical Biochemistry, Medyczna 9, 30-688 Kraków, Poland
| | - Katarzyna Przejczowska-Pomierny
- Jagiellonian University Medical College, Faculty of Pharmacy, Department of Pharmacokinetics and Physical Pharmacy, Medyczna 9, 30-688 Kraków, Poland
| | - Elżbieta Pękala
- Jagiellonian University Medical College, Faculty of Pharmacy, Department of Pharmaceutical Biochemistry, Medyczna 9, 30-688 Kraków, Poland
| | - Reinoud Gosens
- University of Groningen, Department of Molecular Pharmacology, Antonius Deusinglaan 1, 9713 AV Groningen, the Netherlands
| | - Elżbieta Wyska
- Jagiellonian University Medical College, Faculty of Pharmacy, Department of Pharmacokinetics and Physical Pharmacy, Medyczna 9, 30-688 Kraków, Poland
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10
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Weimershaus M, Carvalho C, Rignault R, Waeckel-Enee E, Dussiot M, van Endert P, Maciel TT, Hermine O. Mast cell-mediated inflammation relies on insulin-regulated aminopeptidase controlling cytokine export from the Golgi. J Allergy Clin Immunol 2023:S0091-6749(23)00090-8. [PMID: 36708814 DOI: 10.1016/j.jaci.2023.01.014] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 12/31/2022] [Accepted: 01/11/2023] [Indexed: 01/26/2023]
Abstract
BACKGROUND On activation, mast cells rapidly release preformed inflammatory mediators from large cytoplasmic granules via regulated exocytosis. This acute degranulation is followed by a late activation phase involving synthesis and secretion of cytokines, growth factors, and other inflammatory molecules via the constitutive pathway that remains ill defined. OBJECTIVE We investigated the role for an insulin-responsive vesicle-like endosomal compartment, marked by insulin-regulated aminopeptidase (IRAP), in the secretion of TNF-α and IL-6 in mast cells and macrophages. METHODS Murine knockout (KO) mouse models (IRAP-KO and kit-Wsh/sh) were used to study inflammatory disease models and to measure and mechanistically investigate cytokine secretion and degranulation in bone marrow-derived mast cells in vitro. RESULTS IRAP-KO mice are protected from TNF-α-dependent kidney injury and inflammatory arthritis. In the absence of IRAP, TNF-α and IL-6 but not IL-10 fail to be efficiently secreted. Moreover, chemical targeting of IRAP endosomes reduced proinflammatory cytokine secretion. Mechanistically, impaired TNF-α export from the Golgi and reduced colocalization of vesicle-associated membrane protein (VAMP) 3-positive TNF-α transport vesicles with syntaxin 4 (aka Stx4) was observed in IRAP-KO mast cells, while VAMP8-dependent exocytosis of secretory granules was facilitated. CONCLUSION IRAP plays a novel role in mast cell-mediated inflammation through the regulation of exocytic trafficking of cytokines.
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Affiliation(s)
- Mirjana Weimershaus
- Imagine Institute, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutic Implications, INSERM U1163, F-75015, Paris, France.
| | - Caroline Carvalho
- Imagine Institute, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutic Implications, INSERM U1163, F-75015, Paris, France
| | - Rachel Rignault
- Imagine Institute, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutic Implications, INSERM U1163, F-75015, Paris, France; Université de Paris Cité, Paris, France
| | | | - Michael Dussiot
- Imagine Institute, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutic Implications, INSERM U1163, F-75015, Paris, France; Université de Paris Cité, Paris, France; Laboratory of Excellence GR-Ex, Paris, France
| | - Peter van Endert
- INSERM UMR 1151, CNRS UMR 8253, Paris, France; Université de Paris Cité, Paris, France
| | - Thiago Trovati Maciel
- Imagine Institute, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutic Implications, INSERM U1163, F-75015, Paris, France; Laboratory of Excellence GR-Ex, Paris, France
| | - Olivier Hermine
- Imagine Institute, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutic Implications, INSERM U1163, F-75015, Paris, France; Université de Paris Cité, Paris, France; Hôpital Necker Enfants Malades, Paris, France; Laboratory of Excellence GR-Ex, Paris, France
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11
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Menegati LM, de Oliveira EE, Oliveira BDC, Macedo GC, de Castro E Silva FM. Asthma, obesity, and microbiota: A complex immunological interaction. Immunol Lett 2023; 255:10-20. [PMID: 36646290 DOI: 10.1016/j.imlet.2023.01.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Revised: 01/02/2023] [Accepted: 01/09/2023] [Indexed: 01/15/2023]
Abstract
Obesity and allergic asthma are inflammatory chronic diseases mediated by distinct immunological features, obesity presents a Th1/Th17 profile, asthma is commonly associated with Th2 response. However, when combined, they result in more severe asthma symptoms, greater frequency of exacerbation episodes, and lower therapy responsiveness. These features lead to decreased life quality, associated with higher morbidity/mortality rates. In addition, obesity prompts specific asthma phenotypes, which can be dependent on atopic status, age, and gender. In adults, obesity is associated with neutrophilic/Th17 profile, while in children, the outcome is diverse, in some cases children with obesity present aggravation of atopy, and Th2 inflammation, and in others an association with a Th1 profile, with reduced IgE levels and eosinophilia. These alterations occur due to a complex group of factors among which the microbiome has been recently explored. Particularly, evidence shows its important role in susceptibility or resistance to asthma development, via gut-lung-axis, and demonstrates its relevance to the immune pathogenesis of the syndrome. Few studies address the relevance of the lung microbiome in shaping the immune response, locally. However, specific bacteria, like Moraxella catarrhalis, Haemophilus influenza, and Streptococcus pneumoniae, correlate with important features of the obese-asthmatic phenotype. Although maternal obesity is known to increase asthma risk in offspring, the impact on lung colonization is unknown. This review details the main key immune mechanisms involved in obesity-aggravated asthma, featuring the effect of maternal obesity in the establishment of gut and lung microbiota of the offspring, acting as potential childhood asthma inducer.
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Affiliation(s)
- Laura Machado Menegati
- Faculdade de Medicina, Programa de Pós-Graduação em Saúde, Universidade Federal de Juiz de Fora, MG, Brazil
| | - Erick Esteves de Oliveira
- Instituto de Ciências Biológicas, Programa de Pós-Graduação em Biologia Departamento de Parasitologia, Microbiologia e Imunologia, Universidade Federal de Juiz de Fora MG, Brazil
| | | | - Gilson Costa Macedo
- Instituto de Ciências Biológicas, Programa de Pós-Graduação em Biologia Departamento de Parasitologia, Microbiologia e Imunologia, Universidade Federal de Juiz de Fora MG, Brazil
| | - Flávia Márcia de Castro E Silva
- Departamento de Microbiologia, Imunologia e Parasitologia, Faculdade de Ciências Médicas - RJ, Universidade do Estado do Rio de Janeiro, Brazil.
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12
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Oettgen HC. Mast cells in food allergy: Inducing immediate reactions and shaping long-term immunity. J Allergy Clin Immunol 2023; 151:21-25. [PMID: 36328809 DOI: 10.1016/j.jaci.2022.10.003] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 09/08/2022] [Accepted: 10/04/2022] [Indexed: 11/11/2022]
Abstract
Mast cells are distributed throughout the gastrointestinal tract and function as the main effector cells of IgE-mediated allergic reactions to foods. Allergen-induced cross-linking of IgE antibodies bound to high-affinity IgE receptors, FcεRI, on the surface of mast cells triggers their activation, resulting in the release of mediators of immediate hypersensitivity. These mediators rapidly induce both local gastrointestinal and systemic physiological responses including anaphylaxis. Emerging evidence has revealed that, in addition to inciting immediate reactions, mast cells are key regulators of adaptive immunity to foods. In the gastrointestinal mucosa they provide the priming cytokines that initiate and, over time, consolidate adaptive TH2 responses to ingested allergens as well as TNF and chemokines that orchestrate the recruitment of tissue-infiltrating leukocytes that drive type 2 tissue inflammation. Patients with atopic dermatitis have increased intestinal mast cell numbers and are at a greater risk for food allergy. Recent studies have uncovered a skin-gut axis in which epicutaneous allergen exposure drives intestinal mast cell expansion. The activating effects of IgE antibodies in mast cells are countered by food-specific IgG antibodies that signal via the inhibitory IgG receptor, FcγR2b, suppressing both immediate allergic reactions to foods and the type 2 immune adjuvant activity of mast cells.
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Affiliation(s)
- Hans C Oettgen
- Department of Pediatrics, Boston Children's Hospital, Boston, Mass; Department of Pediatrics, Harvard Medical School, Boston, Mass.
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13
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Joulia R, Guerrero-Fonseca IM, Girbl T, Coates JA, Stein M, Vázquez-Martínez L, Lynam E, Whiteford J, Schnoor M, Voehringer D, Roers A, Nourshargh S, Voisin MB. Neutrophil breaching of the blood vessel pericyte layer during diapedesis requires mast cell-derived IL-17A. Nat Commun 2022; 13:7029. [PMID: 36396641 PMCID: PMC9672103 DOI: 10.1038/s41467-022-34695-7] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Accepted: 11/02/2022] [Indexed: 11/18/2022] Open
Abstract
Neutrophil diapedesis is an immediate step following infections and injury and is driven by complex interactions between leukocytes and various components of the blood vessel wall. Here, we show that perivascular mast cells (MC) are key regulators of neutrophil behaviour within the sub-endothelial space of inflamed venules. Using confocal intravital microscopy, we observe directed abluminal neutrophil motility along pericyte processes towards perivascular MCs, a response that created neutrophil extravasation hotspots. Conversely, MC-deficiency and pharmacological or genetic blockade of IL-17A leads to impaired neutrophil sub-endothelial migration and breaching of the pericyte layer. Mechanistically, identifying MCs as a significant cellular source of IL-17A, we establish that MC-derived IL-17A regulates the enrichment of key effector molecules ICAM-1 and CXCL1 in nearby pericytes. Collectively, we identify a novel MC-IL-17A-pericyte axis as modulator of the final steps of neutrophil diapedesis, with potential translational implications for inflammatory disorders driven by increased neutrophil diapedesis.
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Affiliation(s)
- Régis Joulia
- William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK
- NHLI, Imperial College London, London, UK
| | - Idaira María Guerrero-Fonseca
- William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK
- Department of Molecular Biomedicine, CINVESTAV-IPN, Mexico City, Mexico
| | - Tamara Girbl
- William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK
- Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Würzburg, Germany
| | - Jonathon A Coates
- William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK
| | - Monja Stein
- William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK
| | - Laura Vázquez-Martínez
- William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK
| | - Eleanor Lynam
- William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK
| | - James Whiteford
- William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK
| | - Michael Schnoor
- Department of Molecular Biomedicine, CINVESTAV-IPN, Mexico City, Mexico
| | - David Voehringer
- Department of Infection Biology, University Hospital Erlangen and Friedrich-Alexander University Erlangen-Nuremberg (FAU), Erlangen, 91054, Germany
| | - Axel Roers
- Institute for Immunology, Heidelberg University Hospital, Heidelberg, Germany
| | - Sussan Nourshargh
- William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK
- Centre for Inflammation and Therapeutic Innovation, Queen Mary University of London, London, EC1M 6BQ, UK
| | - Mathieu-Benoit Voisin
- William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK.
- Centre for Inflammation and Therapeutic Innovation, Queen Mary University of London, London, EC1M 6BQ, UK.
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14
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El Ansari YS, Kanagaratham C, Burton OT, Santos JV, Hollister BMA, Lewis OL, Renz H, Oettgen HC. Allergen-Specific IgA Antibodies Block IgE-Mediated Activation of Mast Cells and Basophils. Front Immunol 2022; 13:881655. [PMID: 35865546 PMCID: PMC9294179 DOI: 10.3389/fimmu.2022.881655] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 05/30/2022] [Indexed: 11/13/2022] Open
Abstract
Mast cells and basophils have long been implicated in the pathogenesis of IgE-mediated hypersensitivity reactions. They express the high-affinity IgE receptor, FcϵRI, on their surface. Antigen-induced crosslinking of IgE antibodies bound to that receptor triggers a signaling cascade that results in activation, leading to the release of an array of preformed vasoactive mediators and rapidly synthesized lipids, as well as the de novo production of inflammatory cytokines. In addition to bearing activating receptors like FcεRI, these effector cells of allergy express inhibitory ones including FcγR2b, an IgG Fc receptor with a cytosolic inhibitory motif that activates protein tyrosine phosphatases that suppress IgE-mediated activation. We and others have shown that food allergen-specific IgG antibodies strongly induced during the course of oral immunotherapy (OIT), signal via FcγR2b to suppress IgE-mediated mast cell and basophil activation triggered by food allergen challenge. However, the potential inhibitory effects of IgA antibodies, which are also produced in response to OIT and are present at high levels at mucosal sites, including the intestine where food allergens are encountered, have not been well studied. Here we uncover an inhibitory function for IgA. We observe that IgA binds mouse bone marrow-derived mast cells (BMMCs) and peritoneal mast cells. Binding to BMMCs is dependent on calcium and sialic acid. We also found that IgA antibodies inhibit IgE-mediated mast cell degranulation in an allergen-specific fashion. Antigen-specific IgA inhibits IgE-mediated mast cell activation early in the signaling cascade, suppressing the phosphorylation of Syk, the proximal protein kinase mediating FcεRI signaling, and suppresses mast cell production of cytokines. Furthermore, using basophils from a peanut allergic donor we found that IgA binds to basophils and that activation by exposure to peanuts is effectively suppressed by IgA. We conclude that IgA serves as a regulator of mast cell and basophil degranulation, suggesting a physiologic role for IgA in the maintenance of immune homeostasis at mucosal sites.
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Affiliation(s)
- Yasmeen S. El Ansari
- Division of Immunology, Department of Pediatrics, Boston Children’s Hospital, Boston, MA, United States
- Institute of Laboratory Medicine, Philipps University Marburg, Marburg, Germany
| | - Cynthia Kanagaratham
- Division of Immunology, Department of Pediatrics, Boston Children’s Hospital, Boston, MA, United States
- Department of Pediatrics, Harvard Medical School, Boston, MA, United States
| | - Oliver T. Burton
- Laboratory of Lymphocyte Signaling and Development, The Babraham Institute, Cambridge, United Kingdom
| | - Jenna V. Santos
- Division of Immunology, Department of Pediatrics, Boston Children’s Hospital, Boston, MA, United States
| | | | - Owen L. Lewis
- Division of Immunology, Department of Pediatrics, Boston Children’s Hospital, Boston, MA, United States
| | - Harald Renz
- Institute of Laboratory Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), Philipps University Marburg, German Center for Lung Research (DZL), Marburg, Germany
| | - Hans C. Oettgen
- Division of Immunology, Department of Pediatrics, Boston Children’s Hospital, Boston, MA, United States
- Department of Pediatrics, Harvard Medical School, Boston, MA, United States
- *Correspondence: Hans C. Oettgen,
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15
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Wang C, Hou Y, Ge S, Lu J, Wang X, Lv Y, Wang N, He H. Synthetic imperatorin derivatives alleviate allergic reactions via mast cells. Biomed Pharmacother 2022; 150:112982. [PMID: 35483187 DOI: 10.1016/j.biopha.2022.112982] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 03/23/2022] [Accepted: 04/14/2022] [Indexed: 11/02/2022] Open
Abstract
Anaphylaxis is a severe systemic allergic reaction that exhibits multiple clinical symptoms. The Mas-related G protein-coupled receptor X2 (MRGPRX2) is recognized as a key cell receptor mediating allergic diseases and drug-induced anaphylactoid reactions. Thus, it has been a promising target for preventing and treating these reactions. Based on the potential activity of imperatorin and active structural feature of MRGPRX2, we first demonstrated that the synthetic imperatorin derivatives (IDs) could significantly inhibit MRGPRX2 agonist-induced degranulation and cytokine release in LAD2 cells, as well as alleviate local and systemic anaphylaxis in mice. The IC50 value of the most promising compound is an order of magnitude lower than that of imperatorin. IDs were further identified to display anti-pseudo-allergic activity by binding MRGPRX2 with the tertiary nitrogen substructures, just liking the reported MRGPRX2-ligand. These results would propose evidence for discovery of agents for treating MCs-dependent allergic disorders.
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Affiliation(s)
- Cheng Wang
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Yajing Hou
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Shuai Ge
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Jiayu Lu
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Xiangjun Wang
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Yuexin Lv
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Nan Wang
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Huaizhen He
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.
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16
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Sanin DE, Ge Y, Marinkovic E, Kabat AM, Castoldi A, Caputa G, Grzes KM, Curtis JD, Thompson EA, Willenborg S, Dichtl S, Reinhardt S, Dahl A, Pearce EL, Eming SA, Gerbaulet A, Roers A, Murray PJ, Pearce EJ. A common framework of monocyte-derived macrophage activation. Sci Immunol 2022; 7:eabl7482. [PMID: 35427180 DOI: 10.1126/sciimmunol.abl7482] [Citation(s) in RCA: 68] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Macrophages populate every organ during homeostasis and disease, displaying features of tissue imprinting and heterogeneous activation. The disconnected picture of macrophage biology that has emerged from these observations is a barrier for integration across models or with in vitro macrophage activation paradigms. We set out to contextualize macrophage heterogeneity across mouse tissues and inflammatory conditions, specifically aiming to define a common framework of macrophage activation. We built a predictive model with which we mapped the activation of macrophages across 12 tissues and 25 biological conditions, finding a notable commonality and finite number of transcriptional profiles, in particular among infiltrating macrophages, which we modeled as defined stages along four conserved activation paths. These activation paths include a "phagocytic" regulatory path, an "inflammatory" cytokine-producing path, an "oxidative stress" antimicrobial path, or a "remodeling" extracellular matrix deposition path. We verified this model with adoptive cell transfer experiments and identified transient RELMɑ expression as a feature of monocyte-derived macrophage tissue engraftment. We propose that this integrative approach of macrophage classification allows the establishment of a common predictive framework of monocyte-derived macrophage activation in inflammation and homeostasis.
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Affiliation(s)
- David E Sanin
- Department of Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany.,Department of Oncology, Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Yan Ge
- Institute for Immunology, Medical Faculty Carl Gustav Carus, TU Dresden, Fetscherstr. 74, 01307 Dresden, Germany
| | - Emilija Marinkovic
- Institute for Immunology, Medical Faculty Carl Gustav Carus, TU Dresden, Fetscherstr. 74, 01307 Dresden, Germany
| | - Agnieszka M Kabat
- Department of Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany.,Department of Oncology, Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Angela Castoldi
- Department of Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany
| | - George Caputa
- Department of Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany
| | - Katarzyna M Grzes
- Department of Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany.,Department of Oncology, Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Jonathan D Curtis
- Department of Oncology, Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Elizabeth A Thompson
- Department of Oncology, Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Sebastian Willenborg
- Department of Dermatology, University of Cologne, Kerpenerstr. 62, 50937 Cologne, Germany
| | - Stefanie Dichtl
- Max Planck Institute of Biochemistry, 82152 Martinsried, Germany
| | - Susanne Reinhardt
- DRESDEN-concept Genome Center, TU Dresden, Fetscherstr. 105, 01307 Dresden, Germany
| | - Andreas Dahl
- DRESDEN-concept Genome Center, TU Dresden, Fetscherstr. 105, 01307 Dresden, Germany
| | - Erika L Pearce
- Department of Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany.,Department of Oncology, Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.,Department of Biochemistry and Molecular Biology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21287, USA
| | - Sabine A Eming
- Department of Dermatology, University of Cologne, Kerpenerstr. 62, 50937 Cologne, Germany.,Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.,Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.,Institute of Zoology, Developmental Biology Unit, University of Cologne, Cologne, Germany
| | - Alexander Gerbaulet
- Institute for Immunology, Medical Faculty Carl Gustav Carus, TU Dresden, Fetscherstr. 74, 01307 Dresden, Germany
| | - Axel Roers
- Institute for Immunology, Medical Faculty Carl Gustav Carus, TU Dresden, Fetscherstr. 74, 01307 Dresden, Germany
| | - Peter J Murray
- Max Planck Institute of Biochemistry, 82152 Martinsried, Germany
| | - Edward J Pearce
- Department of Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany.,Department of Oncology, Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.,Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany.,Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21287, USA
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17
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Nakano N, Kitaura J. Mucosal Mast Cells as Key Effector Cells in Food Allergies. Cells 2022; 11:cells11030329. [PMID: 35159139 PMCID: PMC8834119 DOI: 10.3390/cells11030329] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 01/14/2022] [Accepted: 01/18/2022] [Indexed: 12/17/2022] Open
Abstract
Mucosal mast cells (MMCs) localized in the intestinal mucosa play a key role in the development of IgE-mediated food allergies. Recent advances have revealed that MMCs are a distinctly different population from connective tissue mast cells localized in skin and other connective tissues. MMCs are inducible and transient cells that arise from bone marrow-derived mast cell progenitors, and their numbers increase rapidly during mucosal allergic inflammation. However, the mechanism of the dramatic expansion of MMCs and their cell functions are not well understood. Here, we review recent findings on the mechanisms of MMC differentiation and expansion, and we discuss the potential for the inducers of differentiation and expansion to serve as targets for food allergy therapy. In addition, we also discuss the mechanism by which oral immunotherapy, a promising treatment for food allergy patients, induces unresponsiveness to food allergens and the roles of MMCs in this process. Research focusing on MMCs should provide useful information for understanding the underlying mechanisms of food allergies in order to further advance the treatment of food allergies.
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18
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Galli SJ, Gaudenzio N, Tsai M. Mast Cells in Inflammation and Disease: Recent Progress and Ongoing Concerns. Annu Rev Immunol 2021; 38:49-77. [PMID: 32340580 DOI: 10.1146/annurev-immunol-071719-094903] [Citation(s) in RCA: 219] [Impact Index Per Article: 54.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Mast cells have existed long before the development of adaptive immunity, although they have been given different names. Thus, in the marine urochordate Styela plicata, they have been designated as test cells. However, based on their morphological characteristics (including prominent cytoplasmic granules) and mediator content (including heparin, histamine, and neutral proteases), test cells are thought to represent members of the lineage known in vertebrates as mast cells. So this lineage presumably had important functions that preceded the development of antibodies, including IgE. Yet mast cells are best known, in humans, as key sources of mediators responsible for acute allergic reactions, notably including anaphylaxis, a severe and potentially fatal IgE-dependent immediate hypersensitivity reaction to apparently harmless antigens, including many found in foods and medicines. In this review, we briefly describe the origins of tissue mast cells and outline evidence that these cells can have beneficial as well as detrimental functions, both innately and as participants in adaptive immune responses. We also discuss aspects of mast cell heterogeneity and comment on how the plasticity of this lineage may provide insight into its roles in health and disease. Finally, we consider some currently open questions that are yet unresolved.
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Affiliation(s)
- Stephen J Galli
- Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA; , .,Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California 94305, USA.,Sean N. Parker Center for Allergy and Asthma Research, Stanford University School of Medicine, California 94305, USA
| | - Nicolas Gaudenzio
- Unité de Différenciation Epithéliale et Autoimmunité Rhumatoïde (UDEAR), INSERM UMR 1056, Université de Toulouse, 31 059 Toulouse CEDEX 9, France;
| | - Mindy Tsai
- Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA; , .,Sean N. Parker Center for Allergy and Asthma Research, Stanford University School of Medicine, California 94305, USA
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19
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Jeong MJ, Kang SA, Choi JH, Lee DI, Yu HS. Extracellular vesicles of Echinococcus granulosus have therapeutic effects in allergic airway inflammation. Parasite Immunol 2021; 43:e12872. [PMID: 34174101 DOI: 10.1111/pim.12872] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 06/02/2021] [Accepted: 06/18/2021] [Indexed: 11/30/2022]
Abstract
BACKGROUND Previous studies have shown that Echinococcus granulosus cystic fluid can alleviate Th2 allergic airway inflammatory responses by increasing the number of CD4+ CD25+ Foxp3+ T (regulatory T; Treg) cells. Parasite-derived extracellular vesicles (EV) are known to not only promote parasite infection by communicating between parasites but also regulate the inflammatory response by acting as an immunomodulatory agent in the host. METHODS To evaluate the effect of EV extracted from the cystic fluid of E. granulosus on allergic airway inflammation, gene expression was investigated after administering EV to mouse lung epithelial cells (MLE-12) following 2 h of pretreatment with Aspergillus proteins. An allergic airway inflammation animal model was used to investigate the regulation of the inflammatory response by EV and induced with ovalbumin. RESULTS EV treatment significantly reduced airway resistance and the number of eosinophils and other immune cells in the bronchoalveolar lavage fluid and Th2- and Th17-related cytokine levels. EV pretreatment decreased the number of IL-4+ CD4+ T cells and increased the number of Treg cells in the lung-draining lymph nodes and spleen. CONCLUSIONS Echinococcus granulosus cystic fluid derived EV ameliorated Th2 allergic airway inflammatory through Treg cells, similar to whole cystic fluid treatment. Thus, EV may be important immunomodulatory molecules in cystic fluid.
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Affiliation(s)
- Mi Jin Jeong
- Department of Parasitology and Tropical Medicine, School of Medicine, Pusan National University, Yangsan, Republic of Korea
| | - Shin Ae Kang
- Department of Parasitology and Tropical Medicine, School of Medicine, Pusan National University, Yangsan, Republic of Korea
| | - Jun Ho Choi
- Department of Parasitology and Tropical Medicine, School of Medicine, Pusan National University, Yangsan, Republic of Korea
| | - Da In Lee
- Department of Parasitology and Tropical Medicine, School of Medicine, Pusan National University, Yangsan, Republic of Korea
| | - Hak Sun Yu
- Department of Parasitology and Tropical Medicine, School of Medicine, Pusan National University, Yangsan, Republic of Korea.,Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, Republic of Korea
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20
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Mendoza RP, Fudge DH, Brown JM. Cellular Energetics of Mast Cell Development and Activation. Cells 2021; 10:524. [PMID: 33801300 PMCID: PMC7999080 DOI: 10.3390/cells10030524] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 02/23/2021] [Accepted: 02/25/2021] [Indexed: 12/14/2022] Open
Abstract
Mast cells are essential first responder granulocytes in the innate immune system that are well known for their role in type 1 immune hypersensitivity reactions. Although mostly recognized for their role in allergies, mast cells have a range of influences on other systems throughout the body and can respond to a wide range of agonists to properly prime an appropriate immune response. Mast cells have a dynamic energy metabolism to allow rapid responsiveness to their energetic demands. However, our understanding of mast cell metabolism and its impact on mast cell activation and development is still in its infancy. Mast cell metabolism during stimulation and development shifts between both arms of metabolism: catabolic metabolism-such as glycolysis and oxidative phosphorylation-and anabolic metabolism-such as the pentose phosphate pathway. The potential for metabolic pathway shifts to precede and perhaps even control activation and differentiation provides an exciting opportunity to explore energy metabolism for clues in deciphering mast cell function. In this review, we discuss literature pertaining to metabolic environments and fluctuations during different sources of activation, especially IgE mediated vs. non-IgE mediated, and mast cell development, including progenitor cell types leading to the well-known resident mast cell.
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Affiliation(s)
| | | | - Jared M. Brown
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80016, USA; (R.P.M.); (D.H.F.)
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21
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Okunishi K, Wang H, Suzukawa M, Ishizaki R, Kobayashi E, Kihara M, Abe T, Miyazaki JI, Horie M, Saito A, Saito H, Nakae S, Izumi T. Exophilin-5 regulates allergic airway inflammation by controlling IL-33-mediated Th2 responses. J Clin Invest 2021; 130:3919-3935. [PMID: 32240120 DOI: 10.1172/jci127839] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Accepted: 03/31/2020] [Indexed: 12/12/2022] Open
Abstract
A common variant in the RAB27A gene in adults was recently found to be associated with the fractional exhaled nitric oxide level, a marker of eosinophilic airway inflammation. The small GTPase Rab27 is known to regulate intracellular vesicle traffic, although its role in allergic responses is unclear. We demonstrated that exophilin-5, a Rab27-binding protein, was predominantly expressed in both of the major IL-33 producers, lung epithelial cells, and the specialized IL-5 and IL-13 producers in the CD44hiCD62LloCXCR3lo pathogenic Th2 cell population in mice. Exophilin-5 deficiency increased stimulant-dependent damage and IL-33 secretion by lung epithelial cells. Moreover, it enhanced IL-5 and IL-13 production in response to TCR and IL-33 stimulation from a specific subset of pathogenic Th2 cells that expresses a high level of IL-33 receptor, which exacerbated allergic airway inflammation in a mouse model of asthma. Mechanistically, exophilin-5 regulates extracellular superoxide release, intracellular ROS production, and phosphoinositide 3-kinase activity by controlling intracellular trafficking of Nox2-containing vesicles, which seems to prevent the overactivation of pathogenic Th2 cells mediated by IL-33. This is the first report to our knowledge to establish the significance of the Rab27-related protein exophilin-5 in the development of allergic airway inflammation, and provides insights into the pathophysiology of asthma.
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Affiliation(s)
- Katsuhide Okunishi
- Laboratory of Molecular Endocrinology and Metabolism, Department of Molecular Medicine, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan
| | - Hao Wang
- Laboratory of Molecular Endocrinology and Metabolism, Department of Molecular Medicine, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan
| | - Maho Suzukawa
- National Hospital Organization Tokyo National Hospital, Tokyo, Japan.,Division of Respiratory Medicine and Allergology, Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Ray Ishizaki
- Laboratory of Molecular Endocrinology and Metabolism, Department of Molecular Medicine, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan
| | - Eri Kobayashi
- Laboratory of Molecular Endocrinology and Metabolism, Department of Molecular Medicine, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan
| | - Miho Kihara
- Laboratory for Animal Resource Development and
| | - Takaya Abe
- Laboratory for Animal Resource Development and.,Genetic Engineering, RIKEN Center for Biosystems Dynamics Research, Kobe, Japan
| | - Jun-Ichi Miyazaki
- Institute of Scientific and Industrial Research, Osaka University, Osaka, Japan
| | - Masafumi Horie
- Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Akira Saito
- Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Hirohisa Saito
- Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, Tokyo, Japan
| | - Susumu Nakae
- Laboratory of Systems Biology, Center for Experimental Medicine and Systems Biology, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Tetsuro Izumi
- Laboratory of Molecular Endocrinology and Metabolism, Department of Molecular Medicine, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan
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22
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Toyoshima S, Sakamoto-Sasaki T, Kurosawa Y, Hayama K, Matsuda A, Watanabe Y, Terui T, Gon Y, Matsumoto K, Okayama Y. miR103a-3p in extracellular vesicles from FcεRI-aggregated human mast cells enhances IL-5 production by group 2 innate lymphoid cells. J Allergy Clin Immunol 2021; 147:1878-1891. [PMID: 33465368 DOI: 10.1016/j.jaci.2021.01.002] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 12/27/2020] [Accepted: 01/05/2021] [Indexed: 12/21/2022]
Abstract
BACKGROUND Mast cells (MCs) are key regulators of IgE-mediated allergic inflammation. Cell-derived extracellular vesicles (EVs) contain bioactive compounds such as microRNAs. EVs can transfer signals to recipient cells, thus using a novel mechanism of cell-to-cell communication. However, whether MC-derived EVs are involved in FcεRI-mediated allergic inflammation is unclear. OBJECTIVE We sought to investigate the effect of EVs derived from FcεRI-aggregated human MCs on the function of human group 2 innate lymphoid cells (ILC2s). METHODS Human cultured MCs were sensitized with and without IgE for 1 hour and then incubated with anti-IgE antibody, IL-33, or medium alone for 24 hours. EVs in the MC supernatant were isolated by using ExoQuick-TC. RESULTS Coculture of ILC2s with EVs derived from the FcεRI-aggregated MCs significantly enhanced IL-5 production and sustained upregulation of IL-5 mRNA expression in IL-33-stimulated ILC2s, but IL-13 production and IL-13 mRNA expression were unchanged. miR103a-3p expression was upregulated in IL-33-stimulated ILC2s that had been cocultured with EVs derived from anti-IgE antibody-stimulated MCs. Transduction of an miR103a-3p mimic to ILC2s significantly enhanced IL-5 production by IL-33-stimulated ILC2s. miR103a-3p promoted demethylation of an arginine residue of GATA3 by downregulating protein arginine methyltransferase 5 (PRMT5) mRNA. Reduction of protein arginine methyltransferase 5 expression in ILC2s by using a small interfering RNA technique resulted in upregulation of IL-5 production by IL-33-stimulated ILC2s. Furthermore, the level of miR103a-3p expression was significantly higher in EVs from sera of patients with atopic dermatitis than in EVs from nonatopic healthy control subjects. CONCLUSION Eosinophilic allergic inflammation may be exacerbated owing to ILC2 activation by MC-derived miR103a-3p.
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Affiliation(s)
- Shota Toyoshima
- Allergy and Immunology Research Project Team, Research Institute of Medical Science, Nihon University School of Medicine, Tokyo, Japan; Center for Allergy, Nihon University Itabashi Hospital, Tokyo, Japan; Center for Medical Education, Nihon University School of Medicine, Tokyo, Japan
| | - Tomomi Sakamoto-Sasaki
- Allergy and Immunology Research Project Team, Research Institute of Medical Science, Nihon University School of Medicine, Tokyo, Japan; Center for Allergy, Nihon University Itabashi Hospital, Tokyo, Japan; Center for Medical Education, Nihon University School of Medicine, Tokyo, Japan
| | - Yusuke Kurosawa
- Allergy and Immunology Research Project Team, Research Institute of Medical Science, Nihon University School of Medicine, Tokyo, Japan; Center for Allergy, Nihon University Itabashi Hospital, Tokyo, Japan; Division of Respiratory Medicine, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan
| | - Koremasa Hayama
- Center for Allergy, Nihon University Itabashi Hospital, Tokyo, Japan; Divison of Cutaneous Science, Department of Dermatology, Nihon University School of Medicine, Tokyo, Japan
| | - Akira Matsuda
- Department of Ophthalmology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Yasuo Watanabe
- Department of Ophthalmology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Tadashi Terui
- Center for Allergy, Nihon University Itabashi Hospital, Tokyo, Japan; Divison of Cutaneous Science, Department of Dermatology, Nihon University School of Medicine, Tokyo, Japan
| | - Yasuhiro Gon
- Center for Allergy, Nihon University Itabashi Hospital, Tokyo, Japan; Division of Respiratory Medicine, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan
| | - Kenji Matsumoto
- Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, Tokyo, Japan
| | - Yoshimichi Okayama
- Allergy and Immunology Research Project Team, Research Institute of Medical Science, Nihon University School of Medicine, Tokyo, Japan; Center for Allergy, Nihon University Itabashi Hospital, Tokyo, Japan; Center for Medical Education, Nihon University School of Medicine, Tokyo, Japan.
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23
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El Ansari YS, Kanagaratham C, Oettgen HC. Mast Cells as Regulators of Adaptive Immune Responses in Food Allergy. THE YALE JOURNAL OF BIOLOGY AND MEDICINE 2020; 93:711-718. [PMID: 33380933 PMCID: PMC7757069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Mast cells are a critical first line of defense against endogenous and environmental threats. Their participation in innate immunity is well characterized; activation of toll like receptors as well as receptors for complement, adenosine, and a host of other ligands leads to mast cell release of preformed mediators contained within granules along with newly synthesized arachidonic acid metabolites, cytokines, and chemokines. These confer protective effects including the induction of mucus secretion, smooth muscle contraction, and activation of common itch and pain sensations, all of which act to promote expulsion of noxious agents. While their innate immune role as sentinel cells is well established, recent research has brought into focus their separate but also critical function in adaptive immunity particularly in the setting of IgE mediated food allergies. Crosslinking of FcεR1, the high affinity receptor for IgE, when bound to IgE and antigen, triggers the release of the same factors and elicits the same physiologic responses that occur after activation by innate stimuli. Though IgE-activated mast cells are best known for their role in acute allergic reactions, including the most severe manifestation, anaphylaxis, accumulating evidence has suggested an immunoregulatory effect in T cell-mediated immunity, modulating the balance between type 2 immunity and tolerance. In this review, we outline how mast cells act as adjuvants for food antigen driven Th2 cell responses, while curtailing Treg function.
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Affiliation(s)
- Yasmeen S. El Ansari
- Boston Children’s Hospital and Harvard Medical School,
Boston, MA
- Institute of Laboratory Medicine, Philipps University
Marburg, Marburg, Germany
| | - Cynthia Kanagaratham
- Boston Children’s Hospital and Harvard Medical School,
Boston, MA
- Department of Pediatrics, Harvard Medical School,
Boston, MA
| | - Hans C. Oettgen
- Boston Children’s Hospital and Harvard Medical School,
Boston, MA
- Department of Pediatrics, Harvard Medical School,
Boston, MA
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24
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Unno H, Arae K, Matsuda A, Ikutani M, Tamari M, Motomura K, Toyama S, Suto H, Okumura K, Matsuda A, Morita H, Sudo K, Saito H, Matsumoto K, Nakae S. Critical role of IL-33, but not IL-25 or TSLP, in silica crystal-mediated exacerbation of allergic airway eosinophilia. Biochem Biophys Res Commun 2020; 533:493-500. [PMID: 32977946 DOI: 10.1016/j.bbrc.2020.09.046] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Accepted: 09/13/2020] [Indexed: 11/17/2022]
Abstract
Silica crystals (silica), which are a major mineral component of volcanic ash and desert dust, contribute to the pathogenesis of pulmonary disorders such as asthma and fibrosis. Although administration of silica or sand dust to rodents exacerbates development of ovalbumin-induced or house dust mite-induced asthma-like airway inflammation, the detailed mechanisms remain unclear. Here, using murine models, we found that silica can induce IL-33 expression in pulmonary epithelial cells. IL-33, but not IL-25 or TSLP, and type 2 cytokines such as IL-5 and IL-13 were critically involved in silica's exacerbation of OVA-induced airway eosinophilia in mice. Innate lymphoid cells (ILCs), but not T, B or NKT cells, were also involved in the setting. Moreover, a scavenger receptor that recognized silica was important for silica's exacerbating effect. These observations suggest that IL-33 induced in epithelial cells by silica activates ILCs to produce IL-5 and/or IL-13, contributing to silica's exacerbation of OVA-induced airway eosinophilia in mice. Our findings provide new insight into the underlying mechanisms of exacerbation of pulmonary disorders such as asthma following inhalation of silica-containing materials such as volcanic ash and desert dust.
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Affiliation(s)
- Hirotoshi Unno
- Department of Pediatrics, The Jikei University School of Medicine, Tokyo, 105-8461, Japan; Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, Tokyo, 157-8535, Japan
| | - Ken Arae
- Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, Tokyo, 157-8535, Japan; Department of Immunology, Faculty of Health Sciences, Kyorin University, Tokyo, 181-8612, Japan
| | - Akira Matsuda
- Laboratory of Ocular Atopic Diseases, Department of Ophthalmology, Juntendo University School, Tokyo, 113-8412, Japan
| | - Masashi Ikutani
- Graduate School of Integrated Sciences for Life, Hiroshima University, Hiroshima, 739-8528, Japan
| | - Masato Tamari
- Department of Pediatrics, The Jikei University School of Medicine, Tokyo, 105-8461, Japan; Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, Tokyo, 157-8535, Japan
| | - Kenichiro Motomura
- Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, Tokyo, 157-8535, Japan
| | - Sumika Toyama
- Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, Tokyo, 157-8535, Japan
| | - Hajime Suto
- Atopy Research Center, Graduate School of Medicine, Juntendo University, Tokyo, 113-8412, Japan
| | - Ko Okumura
- Atopy Research Center, Graduate School of Medicine, Juntendo University, Tokyo, 113-8412, Japan
| | - Akio Matsuda
- Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, Tokyo, 157-8535, Japan
| | - Hideaki Morita
- Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, Tokyo, 157-8535, Japan
| | - Katsuko Sudo
- Animal Research Center, Tokyo Medical University, Tokyo, 160-8402, Japan
| | - Hirohisa Saito
- Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, Tokyo, 157-8535, Japan
| | - Kenji Matsumoto
- Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, Tokyo, 157-8535, Japan
| | - Susumu Nakae
- Graduate School of Integrated Sciences for Life, Hiroshima University, Hiroshima, 739-8528, Japan; Laboratory of Systems Biology, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan; Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Saitama, 332-0012, Japan.
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25
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Shi S, Xue L, Han S, Qiu H, Peng Y, Zhao P, Liu QH, Shen J. Anti-Contractile and Anti-Inflammatory Effects of Diacerein on Isolated Mouse Airways Smooth Muscle and Mouse Asthma Model. Front Pharmacol 2020; 11:560361. [PMID: 33013396 PMCID: PMC7498646 DOI: 10.3389/fphar.2020.560361] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Accepted: 08/18/2020] [Indexed: 01/27/2023] Open
Abstract
Characterized by abnormal smooth muscle contractility and airway inflammation, asthma is one of the most common airway diseases worldwide. Diacerein is a well-known anti-inflammatory drug, widely used in osteoarthritis. In current study, the innovative usage of diacerein in anti-contractile and anti-inflammatory treatment of asthma was studied. In vitro experiments including tension measurement and patch-clamp technique and in vivo experiments including establishment of mice model and measurement of respiratory resistance were applied to explore the role of diacerein in asthma. It turned out that agonist-precontracted mouse airway smooth muscle could be relaxed by diacerein via intracellular and extracellular calcium mobilization which was mediated by switched voltage-dependent L-type Ca2+ channels, non-selective cation channels, large-conductance Ca2+-activated K+ channel, and Na+/Ca2+ exchangers. Furthermore, diacerein could relieve bronchospasm and control airway inflammation in asthmatic mice via reduction of several inflammatory factors. Our studies elucidated the potential therapeutic property of diacerein in asthma treatment and the possible underlying mechanism. It also confirmed that new uses for already-approved drugs could be an important form of innovation.
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Affiliation(s)
- Shunbo Shi
- Institute for Medical Biology and Hubei Provincial Key Laboratory for Protection and Application of Special Plants in Wuling Area of China, College of Life Sciences, South-Central University for Nationalities, Wuhan, China
| | - Lu Xue
- Institute for Medical Biology and Hubei Provincial Key Laboratory for Protection and Application of Special Plants in Wuling Area of China, College of Life Sciences, South-Central University for Nationalities, Wuhan, China
| | - Shuhui Han
- Institute for Medical Biology and Hubei Provincial Key Laboratory for Protection and Application of Special Plants in Wuling Area of China, College of Life Sciences, South-Central University for Nationalities, Wuhan, China
| | - Haiting Qiu
- Institute for Medical Biology and Hubei Provincial Key Laboratory for Protection and Application of Special Plants in Wuling Area of China, College of Life Sciences, South-Central University for Nationalities, Wuhan, China
| | - Yongbo Peng
- Institute for Medical Biology and Hubei Provincial Key Laboratory for Protection and Application of Special Plants in Wuling Area of China, College of Life Sciences, South-Central University for Nationalities, Wuhan, China
| | - Ping Zhao
- Institute for Medical Biology and Hubei Provincial Key Laboratory for Protection and Application of Special Plants in Wuling Area of China, College of Life Sciences, South-Central University for Nationalities, Wuhan, China
| | - Qing-Hua Liu
- Institute for Medical Biology and Hubei Provincial Key Laboratory for Protection and Application of Special Plants in Wuling Area of China, College of Life Sciences, South-Central University for Nationalities, Wuhan, China
| | - Jinhua Shen
- Institute for Medical Biology and Hubei Provincial Key Laboratory for Protection and Application of Special Plants in Wuling Area of China, College of Life Sciences, South-Central University for Nationalities, Wuhan, China
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26
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Svanberg S, Li Z, Öhlund P, Roy A, Åbrink M. Mast Cells Limit Ear Swelling Independently of the Chymase Mouse Mast Cell Protease 4 in an MC903-Induced Atopic Dermatitis-Like Mouse Model. Int J Mol Sci 2020; 21:ijms21176311. [PMID: 32878208 PMCID: PMC7503626 DOI: 10.3390/ijms21176311] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 08/20/2020] [Accepted: 08/26/2020] [Indexed: 12/31/2022] Open
Abstract
Atopic dermatitis (AD) is a complex, often lifelong allergic disease with severe pruritus affecting around 10% of both humans and dogs. To investigate the role of mast cells (MCs) and MC-specific proteases on the immunopathogenesis of AD, a vitamin D3-analog (MC903) was used to induce clinical AD-like symptoms in c-kit-dependent MC-deficient Wsh−/− and the MC protease-deficient mMCP-4−/−, mMCP-6−/−, and CPA3−/− mouse strains. MC903-treatment on the ear lobe increased clinical scores and ear-thickening, along with increased MC and granulocyte infiltration and activity, as well as increased levels of interleukin 33 (IL-33) locally and thymic stromal lymphopoietin (TSLP) both locally and systemically. The MC-deficient Wsh−/− mice showed significantly increased clinical score and ear thickening albeit having lower ear tissue levels of IL-33 and TSLP as well as lower serum levels of TSLP as compared to the WT mice. In contrast, although having significantly increased IL-33 ear tissue levels the chymase-deficient mMCP-4−/− mice showed similar clinical score, ear thickening, and TSLP levels in ear tissue and serum as the WT mice, whereas mMCP-6 and CPA3 -deficient mice showed a slightly reduced ear thickening and granulocyte infiltration. Our results suggest that MCs promote and control the level of MC903-induced AD-like inflammation.
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Affiliation(s)
- Sofie Svanberg
- Evidensia Djurkliniken Öjebyn, Öjagatan 81, 94331 Öjebyn, Sweden;
- Section of Immunology, Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, VHC, Box 7028, 75007 Uppsala, Sweden;
| | - Zhiqiang Li
- Section of Immunology, Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, VHC, Box 7028, 75007 Uppsala, Sweden;
- Department of Immunology, School of Basic Medical Sciences, Guizhou Medical University, 550025 Guiyang, China
| | - Pontus Öhlund
- Section of Virology, Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, VHC, Box 7028, 75007 Uppsala, Sweden;
| | - Ananya Roy
- Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, 75185 Uppsala, Sweden;
| | - Magnus Åbrink
- Section of Immunology, Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, VHC, Box 7028, 75007 Uppsala, Sweden;
- Correspondence: ; Tel.: +46-70-673-6569
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27
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Feng S, Ju L, Shao Z, Grzanna M, Jia L, Liu M. Therapeutic Effect of C-C Chemokine Receptor Type 1 (CCR1) Antagonist BX471 on Allergic Rhinitis. J Inflamm Res 2020; 13:343-356. [PMID: 32801828 PMCID: PMC7398876 DOI: 10.2147/jir.s254717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Accepted: 06/26/2020] [Indexed: 11/23/2022] Open
Abstract
Objective and Design Allergic rhinitis (AR) is an immunoglobulin E (IgE)-mediated inflammatory respiratory hypersensitivity characterized by elevated Th2 cytokines and infiltration of inflammatory cells to nasal tissues. BX471 is a small-molecule C-C chemokine receptor type 1 (CCR1) antagonist involved in suppression of inflammation via blocking of primary ligands. In this study, we examined the anti-inflammatory effect of BX471 on ovalbumin (OVA)-induced AR mice model. Materials and Methods Levels of OVA-specific IgE and Th1 cytokines were determined by enzyme-linked immunosorbent assay (ELISA). Nasal expression of proinflammatory mediators was assessed by real-time polymerase chain reaction (RT-qPCR). Nasal-cavity sections were stained with hematoxylin and eosin (HE) and periodic acid-Schiff (PAS) to study eosinophil infiltration and goblet cell metaplasia. Relative protein levels of Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-kB), Toll-like Receptor 4 (TLR4) and Toll-like-receptor 2 (TLR2) were assessed by Western Blot. Percentage of CD4+CD25+Foxp3+ T regulatory cells (Treg) was measured by flow cytometry. Results Mice treated with BX471 showed significantly relieved sneezing and nasal-rubbing behaviors. The expression of nasal proinflammatory factors was significantly downregulated by BX471, and protein levels of tumor necrosis factor alpha (TNF- α) and NF-kB were suppressed. Blockade of CCR1 ligands inhibited eosinophil recruitment in nasal cavity. In addition, Treg cells population were upregulated in BX471-treated mice. Conclusion BX471 exerts anti-inflammatory effects in a mouse model of AR by inhibiting CCR1-mediated TNF-α production, which subsequently suppresses NF-kB activation in inflammatory cells, leading to a decrease in Th2 cytokines, IL-1β, VCAM-1, GM-CSF, RANTES, and MIP-1α expression levels, thus inhibiting eosinophil recruitment to nasal mucosa. In addition, BX-471 exhibits anti-allergic effect by increasing Treg cell population. Overall, BX471 represents a promising therapeutic strategy against AR. ![]()
Point your SmartPhone at the code above. If you have a QR code reader the video abstract will appear. Or use: https://youtu.be/ERjzrETqVkE
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Affiliation(s)
- Suoyi Feng
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, Heilongjiang Province 150030, People's Republic of China.,Science Department, The John Carroll School, Bel Air, Maryland, USA
| | - Longzhu Ju
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, Heilongjiang Province 150030, People's Republic of China
| | - Ziqi Shao
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, Heilongjiang Province 150030, People's Republic of China.,College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei Province 430070, People's Republic of China
| | - Mark Grzanna
- Science Department, The John Carroll School, Bel Air, Maryland, USA
| | - Lu Jia
- School of Basic Medical Science, Shanxi University of Traditional Chinese Medicine, Jinzhong, Shanxi Province 030619, People's Republic of China
| | - Ming Liu
- State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin, Heilongjiang Province 150069, People's Republic of China
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Park HH, Lee S, Yu Y, Yoo SM, Baek SY, Jung N, Seo KW, Kang KS. TGF-β secreted by human umbilical cord blood-derived mesenchymal stem cells ameliorates atopic dermatitis by inhibiting secretion of TNF-α and IgE. Stem Cells 2020; 38:904-916. [PMID: 32277785 DOI: 10.1002/stem.3183] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 03/03/2020] [Accepted: 03/17/2020] [Indexed: 12/20/2022]
Abstract
Human mesenchymal stem cells (MSCs) are promising therapeutics for autoimmune diseases due to their immunomodulatory effects. In particular, human umbilical cord blood-derived MSCs (hUCB-MSCs) have a prominent therapeutic effect on atopic dermatitis (AD). However, the underlying mechanism is unclear. This study investigated the role of transforming growth factor-beta (TGF-β) in the therapeutic effect of hUCB-MSCs on AD. Small interfering RNA (siRNA)-mediated depletion of TGF-β disrupted the therapeutic effect of hUCB-MSCs in a mouse model of AD by attenuating the beneficial changes in histopathology, mast cell infiltration, tumor necrosis factor-alpha (TNF-α) expression, and the serum IgE level. To confirm that hUCB-MSCs regulate secretion of TNF-α, we investigated whether they inhibit TNF-α secretion by activated LAD2 cells. Coculture with hUCB-MSCs significantly inhibited secretion of TNF-α by LAD2 cells. However, this effect was abolished by siRNA-mediated depletion of TGF-β in hUCB-MSCs. TNF-α expression in activated LAD2 cells was regulated by the extracellular signal-related kinase signaling pathway and was suppressed by TGF-β secreted from hUCB-MSCs. In addition, TGF-β secreted by hUCB-MSCs inhibited maturation of B cells. Taken together, our findings suggest that TGF-β plays a key role in the therapeutic effect of hUCB-MSCs on AD by regulating TNF-α in mast cells and maturation of B cells.
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Affiliation(s)
- Hwan Hee Park
- Stem Cell and Regenerative Bioengineering Institute, Kangstem Biotech Co., Ltd., Biotechnology Center, Seoul National University, Seoul, South Korea
| | - Seunghee Lee
- Stem Cell and Regenerative Bioengineering Institute, Kangstem Biotech Co., Ltd., Biotechnology Center, Seoul National University, Seoul, South Korea
| | - Yeonsil Yu
- Stem Cell and Regenerative Bioengineering Institute, Kangstem Biotech Co., Ltd., Biotechnology Center, Seoul National University, Seoul, South Korea
| | - Sae Mi Yoo
- Stem Cell and Regenerative Bioengineering Institute, Kangstem Biotech Co., Ltd., Biotechnology Center, Seoul National University, Seoul, South Korea
| | - Song Yi Baek
- Stem Cell and Regenerative Bioengineering Institute, Kangstem Biotech Co., Ltd., Biotechnology Center, Seoul National University, Seoul, South Korea
| | - Namhee Jung
- Stem Cell and Regenerative Bioengineering Institute, Kangstem Biotech Co., Ltd., Biotechnology Center, Seoul National University, Seoul, South Korea
| | - Kwang-Won Seo
- Stem Cell and Regenerative Bioengineering Institute, Kangstem Biotech Co., Ltd., Biotechnology Center, Seoul National University, Seoul, South Korea
| | - Kyung-Sun Kang
- Stem Cell and Regenerative Bioengineering Institute, Kangstem Biotech Co., Ltd., Biotechnology Center, Seoul National University, Seoul, South Korea
- Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul, South Korea
- Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, South Korea
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Wang J, Zhang Y, Zeng Y, Ge S, Sun X, Jia M, Wu Y, Wang N. Isoimperatorin reduces the effective dose of dexamethasone in a murine model of asthma by inhibiting mast cell activation. Phytother Res 2020; 34:2985-2997. [PMID: 32491281 DOI: 10.1002/ptr.6726] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Revised: 04/03/2020] [Accepted: 04/25/2020] [Indexed: 01/18/2023]
Abstract
Adverse effects that result from dexamethasone (DEX) use are common and serious in patients with asthma. Therefore, alternative anti-inflammatory treatments are being investigated. Isoimperatorin (ISO), an active natural furocoumarin, possesses multiple pharmacological properties, including an anti-inflammation effect. In this study, investigations were conducted on the effect of ISO on mast cell (MC) activation in vitro and whether ISO could reduce the effective dose of DEX in a mast cell-dependent murine model of asthma in vivo. Calcium imaging was used to assess intracellular Ca2+ mobilization. Enzyme-linked immunosorbent assay was used to measure the chemokines release. Western blot analysis was conducted to investigate the underlying pathway. Airway inflammation and hyperresponsiveness (AHR) were examined in an asthma model. ISO inhibited Ca2+ flux and MC degranulation via Lyn/PLCγ1/PKC, ERK, and P38 MAPK pathways. In the asthma model, ISO, in combination with DEX, showed an additive inhibitory effect on AHR, inflammation, and the number of activated MCs in the lungs and decreased the levels of interleukin (IL)-4, IL-5, IL-6, IL-13, tumor necrosis factor (TNF)-a, and C-C motif chemokine ligand (CCL)-2 in bronchoalveolar lavage fluid. A combination of DEX and ISO may be appropriate if a decrease in the steroid dose is desired owing to dose-dependent adverse effects.
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Affiliation(s)
- Jue Wang
- College of Pharmacy, Xi'an Jiaotong University, Xi'an, China
| | - Yongjing Zhang
- College of Pharmacy, Xi'an Jiaotong University, Xi'an, China
| | - Yingnan Zeng
- College of Pharmacy, Xi'an Jiaotong University, Xi'an, China
| | - Shuai Ge
- College of Pharmacy, Xi'an Jiaotong University, Xi'an, China
| | - Xiuzhen Sun
- Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Min Jia
- Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an, China
| | - Yuanyuan Wu
- Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Nan Wang
- College of Pharmacy, Xi'an Jiaotong University, Xi'an, China
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Endomorphin-2- and Neurotensin- Based Chimeric Peptide Attenuates Airway Inflammation in Mouse Model of Nonallergic Asthma. Int J Mol Sci 2019; 20:ijms20235935. [PMID: 31779093 PMCID: PMC6929018 DOI: 10.3390/ijms20235935] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 11/19/2019] [Accepted: 11/22/2019] [Indexed: 11/21/2022] Open
Abstract
We examined anti-inflammatory potency of hybrid peptide-PK20, composed of neurotensin (NT) and endomorphin-2 (EM-2) pharmacophores in a murine model of non-atopic asthma induced by skin sensitization with 2,4-dinitrofluorobenzene and intratracheal challenge of cognate hapten. Mice received intraperitoneally PK20, equimolar mixture of its structural elements (MIX), dexamethasone (DEX), or NaCl. Twenty-four hours following hapten challenge, the measurements of airway responsiveness to methacholine were taken. Bronchoalveolar lavage (BALF) and lungs were collected for further analyses. Treatment with PK20, similarly to dexamethasone, reduced infiltration of inflammatory cells, concentration of mouse mast cell protease, IL-1β, IL-12p40, IL-17A, CXCL1, RANTES in lungs and IL-1α, IL-2, IL-13, and TNF-α in BALF. Simple mixture of NT and EM-2 moieties was less potent. PK20, DEX, and MIX significantly decreased malondialdehyde level and secretory phospholipase 2 activity in lungs. Intensity of NF-κB immunoreactivity was diminished only after PK20 and DEX treatments. Neither PK20 nor mixture of its pharmacophores were as effective as DEX in alleviating airway hyperresponsiveness. PK20 effectively inhibited hapten-induced inflammation and mediator and signaling pathways in a manner seen with dexamethasone. Improved anti-inflammatory potency of the hybrid over the mixture of its moieties shows its preponderance and might pose a promising tool in modulating inflammation in asthma.
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Mast cells drive IgE-mediated disease but might be bystanders in many other inflammatory and neoplastic conditions. J Allergy Clin Immunol 2019; 144:S19-S30. [DOI: 10.1016/j.jaci.2019.07.017] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Revised: 06/11/2019] [Accepted: 07/08/2019] [Indexed: 01/05/2023]
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Méndez-Enríquez E, Hallgren J. Mast Cells and Their Progenitors in Allergic Asthma. Front Immunol 2019; 10:821. [PMID: 31191511 PMCID: PMC6548814 DOI: 10.3389/fimmu.2019.00821] [Citation(s) in RCA: 146] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Accepted: 03/28/2019] [Indexed: 12/16/2022] Open
Abstract
Mast cells and their mediators have been implicated in the pathogenesis of asthma and allergy for decades. Allergic asthma is a complex chronic lung disease in which several different immune cells, genetic factors and environmental exposures influence the pathology. Mast cells are key players in the asthmatic response through secretion of a multitude of mediators with pro-inflammatory and airway-constrictive effects. Well-known mast cell mediators, such as histamine and bioactive lipids are responsible for many of the physiological effects observed in the acute phase of allergic reactions. The accumulation of mast cells at particular sites of the allergic lung is likely relevant to the asthma phenotype, severity and progression. Mast cells located in different compartments in the lung and airways have different characteristics and express different mediators. According to in vivo experiments in mice, lung mast cells develop from mast cell progenitors induced by inflammatory stimuli to migrate to the airways. Human mast cell progenitors have been identified in the blood circulation. A high frequency of circulating human mast cell progenitors may reflect ongoing pathological changes in the allergic lung. In allergic asthma, mast cells become activated mainly via IgE-mediated crosslinking of the high affinity receptor for IgE (FcεRI) with allergens. However, mast cells can also be activated by numerous other stimuli e.g. toll-like receptors and MAS-related G protein-coupled receptor X2. In this review, we summarize research with implications on the role and development of mast cells and their progenitors in allergic asthma and cover selected activation pathways and mast cell mediators that have been implicated in the pathogenesis. The review places an emphasis on describing mechanisms identified using in vivo mouse models and data obtained by analysis of clinical samples.
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Affiliation(s)
- Erika Méndez-Enríquez
- Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
| | - Jenny Hallgren
- Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
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Maehara T, Nakamura T, Maeda S, Aritake K, Nakamura M, Murata T. Epithelial cell-derived prostaglandin D 2 inhibits chronic allergic lung inflammation in mice. FASEB J 2019; 33:8202-8210. [PMID: 31018708 DOI: 10.1096/fj.201802817r] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
The precise role of prostaglandin D (PGD)2 in allergic lung inflammation remains controversial. Here, we aimed to clarify the role of PGD2 in chronic allergic lung inflammation using hematopoietic PGD synthase (H-PGDS)-deficient mice. Repeated intranasal administration of ovalbumin (OVA) resulted in eosinophilic infiltration and mucin production in the lungs of wild type (WT) mice, leading to respiratory dysfunction. H-PGDS deficiency exacerbated these effects, which were accompanied by increased mRNA expression of TNF-α and eosinophil chemoattractants. The bronchial epithelium expressed both H-PGDS and TNF-α in the inflamed WT lung, and H-PGDS deficiency increased TNF-α expression further. In cultured bronchial tissue of WT mice, treatment with LPS elevated mRNA expression of TNF-α and eosinophil chemoattractants. H-PGDS deficiency promoted the expression of these factors, which was inhibited by treatment with PGD2 receptor, D prostanoid (DP) receptor agonist, or PGD2 metabolite 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2). Treatment with TNF-α receptor antibody inhibited eosinophil chemoattractant expression. In vivo, administration of DP agonist or 15d-PGJ2 inhibited OVA-induced allergic lung inflammation. Bronchial epithelial cell-derived PGD2 attenuated lung eosinophilic infiltration with chronic allergic inflammation; these phenomena are at least partly attributed to the inhibition of TNF-α production via DP activation or 15-deoxy-Δ12,14-PGJ2 signaling.-Maehara, T., Nakamura, T., Maeda, S., Aritake, K., Nakamura, M., Murata, T. Epithelial cell-derived prostaglandin D2 inhibits chronic allergic lung inflammation in mice.
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Affiliation(s)
- Toko Maehara
- Department of Animal Radiology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan.,Department of Pathobiochemistry, Osaka University of Pharmaceutical Sciences, Osaka, Japan
| | - Tatsuro Nakamura
- Department of Animal Radiology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Shingo Maeda
- Department of Animal Radiology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Kosuke Aritake
- Laboratory of Chemical Pharmacology, Daiichi University of Pharmacy, Fukuoka, Japan
| | - Masataka Nakamura
- Human Gene Sciences Center, Tokyo Medical and Dental University, Tokyo, Japan
| | - Takahisa Murata
- Department of Animal Radiology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
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Uchida K, Takano S, Inoue G, Iwase D, Aikawa J, Takata K, Tazawa R, Kawakubo A, Sekiguchi H, Takaso M. Increase in mast cell marker expression in the synovium of obese patients with osteoarthritis of the knee. Diabetes Metab Syndr Obes 2019; 12:377-382. [PMID: 31114272 PMCID: PMC6497865 DOI: 10.2147/dmso.s201523] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Accepted: 03/04/2019] [Indexed: 11/23/2022] Open
Abstract
Purpose: While research suggests that obesity is a risk factor for knee osteoarthritis (KOA), the mechanisms are not fully understood. Mast cell (MC) numbers are increased in the osteoarthritic synovium and in the adipose tissue of obese individuals. We hypothesized that MC numbers are increased in the synovium of obese KOA patients. This study investigated MC marker and MC-generated cytokine/growth factor expression in the synovium of obese KOA patients. Patients and methods: Patients radiographically diagnosed with KOA (male: 38, female: 132) were allocated to three groups based on their body mass index (BMI): normal (<25 kg/m2), overweight (25-29.99 kg/m2) and obese (≥30 kg/m2), according to the World Health Organization BMI classification. We used real-time polymerase chain reaction to compare the expression of MC markers (CD117, CD203c) and growth factors/cytokines (FGF2, VEGFA, TNFA, and IL8) in patients' synovium among the groups. Results: CD117 expression was significantly higher in the obese group than in the normal and overweight groups. CD203c and FGF2 expression were higher in the obese group than in the normal group. FGF2 expression levels were significantly correlated with those of CD117 (ρ=0.487) and CD203c (ρ=0.751). Conclusion: MC markers CD117 and CD203c, and FGF2 were highly expressed in the synovium of obese KOA patients. Further investigations are needed to reveal the role of MCs in the relationship between obesity and osteoarthritis pathology.
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Affiliation(s)
- Kentaro Uchida
- Department of Orthopedic Surgery, Kitasato University School of Medicine, Sagamihara City, Kanagawa252–0374, Japan
- Correspondence: Kentaro Uchida Department of Orthopedic Surgery Kitasato University School of Medicine, Kentaro Uchida 1–15–1 Minami-ku, Kitasato, Sagamihara City, Kanagawa252–0374, JapanTel +81 042 778 9217Fax +81 042 778 9217Email
| | - Shotaro Takano
- Department of Orthopedic Surgery, Kitasato University School of Medicine, Sagamihara City, Kanagawa252–0374, Japan
| | - Gen Inoue
- Department of Orthopedic Surgery, Kitasato University School of Medicine, Sagamihara City, Kanagawa252–0374, Japan
| | - Dai Iwase
- Department of Orthopedic Surgery, Kitasato University School of Medicine, Sagamihara City, Kanagawa252–0374, Japan
| | - Jun Aikawa
- Department of Orthopedic Surgery, Kitasato University School of Medicine, Sagamihara City, Kanagawa252–0374, Japan
| | - Ken Takata
- Department of Orthopedic Surgery, Kitasato University School of Medicine, Sagamihara City, Kanagawa252–0374, Japan
| | - Ryo Tazawa
- Department of Orthopedic Surgery, Kitasato University School of Medicine, Sagamihara City, Kanagawa252–0374, Japan
| | - Ayumu Kawakubo
- Department of Orthopedic Surgery, Kitasato University School of Medicine, Sagamihara City, Kanagawa252–0374, Japan
| | - Hiroyuki Sekiguchi
- Shonan University of Medical Sciences Research Institute, Chigasaki City, Kanagawa253–0083, Japan
| | - Masashi Takaso
- Department of Orthopedic Surgery, Kitasato University School of Medicine, Sagamihara City, Kanagawa252–0374, Japan
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Schubert N, Lisenko K, Auerbach C, Weitzmann A, Ghouse SM, Muhandes L, Haase C, Häring T, Schulze L, Voehringer D, Gunzer F, Müller W, Feyerabend TB, Rodewald HR, Dudeck A, Roers A. Unimpaired Responses to Vaccination With Protein Antigen Plus Adjuvant in Mice With Kit-Independent Mast Cell Deficiency. Front Immunol 2018; 9:1870. [PMID: 30210490 PMCID: PMC6123530 DOI: 10.3389/fimmu.2018.01870] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2018] [Accepted: 07/30/2018] [Indexed: 12/23/2022] Open
Abstract
Innate inflammatory responses are crucial for induction and regulation of T cell and antibody responses. Mast cell (MC)-deficient Kit mutant mice showed impaired adaptive immunity, suggesting that MCs provide essential adjuvant activities, and pharmacological MC activation was proposed as a new adjuvant principle. However, the Kit mutations result in complex alterations of the immune system in addition to MC deficiency. We revisited the role of MCs in vaccination responses using Mcpt5-Cre R26DTA/DTA and Cpa3Cre/+ mice that lack connective tissue MCs or all MCs, respectively, but feature an otherwise normal immune system. These animals showed no impairment of T and B cell responses to intradermal vaccination with protein antigen plus complete Freund’s adjuvant. Moreover, we demonstrate that the adjuvant effects of the MC secretagogue c48/80 in intradermal or mucosal immunization are independent of the presence of MCs. We hence find no evidence for a regulation by MCs of adaptive immune responses to protein antigens. The finding that immunological MC functions differ from those suggested by experiments in Kit mutants, emphasizes the importance of rigorous tests in Kit-independent MC-deficiency models.
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Affiliation(s)
- Nadja Schubert
- Medical Faculty Carl Gustav Carus, Institute for Immunology, University of Technology Dresden, Dresden, Germany
| | - Katharina Lisenko
- Medical Faculty Carl Gustav Carus, Institute for Immunology, University of Technology Dresden, Dresden, Germany
| | - Christian Auerbach
- Medical Faculty Carl Gustav Carus, Institute of Medical Microbiology and Hygiene, University of Technology Dresden, Dresden, Germany
| | - Anke Weitzmann
- Medical Faculty Carl Gustav Carus, Institute for Immunology, University of Technology Dresden, Dresden, Germany
| | - Shanawaz Mohammed Ghouse
- Medical Faculty Carl Gustav Carus, Institute for Immunology, University of Technology Dresden, Dresden, Germany
| | - Lina Muhandes
- Medical Faculty Carl Gustav Carus, Institute for Immunology, University of Technology Dresden, Dresden, Germany
| | - Christa Haase
- Medical Faculty Carl Gustav Carus, Institute for Immunology, University of Technology Dresden, Dresden, Germany
| | - Tobias Häring
- Medical Faculty Carl Gustav Carus, Institute for Immunology, University of Technology Dresden, Dresden, Germany
| | - Livia Schulze
- Medical Faculty Carl Gustav Carus, Institute for Immunology, University of Technology Dresden, Dresden, Germany
| | - David Voehringer
- Department of Infection Biology, University Hospital Erlangen and Friedrich-Alexander University Erlangen-Nuremberg (FAU), Erlangen, Germany
| | - Florian Gunzer
- Medical Faculty Carl Gustav Carus, Institute of Medical Microbiology and Hygiene, University of Technology Dresden, Dresden, Germany
| | - Werner Müller
- Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom
| | | | - Hans-Reimer Rodewald
- Division of Cellular Immunology, German Cancer Research Center, Heidelberg, Germany
| | - Anne Dudeck
- Medical Faculty Carl Gustav Carus, Institute for Immunology, University of Technology Dresden, Dresden, Germany.,Medical Faculty, Institute for Molecular and Clinical Immunology, Otto von Guericke University, Magdeburg, Germany
| | - Axel Roers
- Medical Faculty Carl Gustav Carus, Institute for Immunology, University of Technology Dresden, Dresden, Germany
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Arae K, Morita H, Unno H, Motomura K, Toyama S, Okada N, Ohno T, Tamari M, Orimo K, Mishima Y, Suto H, Okumura K, Sudo K, Miyazawa H, Taguchi H, Saito H, Matsumoto K, Nakae S. Chitin promotes antigen-specific Th2 cell-mediated murine asthma through induction of IL-33-mediated IL-1β production by DCs. Sci Rep 2018; 8:11721. [PMID: 30082755 PMCID: PMC6079063 DOI: 10.1038/s41598-018-30259-2] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2018] [Accepted: 07/26/2018] [Indexed: 12/15/2022] Open
Abstract
Chitin, which is a major component of house dust mites (HDM), fungi, crustaceans, etc., can activate immune cells, suggesting that it contributes to development of allergic disorders such as asthma. Although the pathophysiological sensitization route of asthmatic patients to allergens is considered via the respiratory tract, the roles of intranasally-administered chitin in development of asthma remain unclear. After ovalbumin (OVA) challenge, development of airway inflammation was profoundly exacerbated in mice sensitized with OVA in the presence of chitin. The exacerbation was dependent on IL-33, but not IL-25, thymic stromal lymphopoietin or IL-17A. Chitin enhanced IL-33-dependent IL-1β production by dendritic cells (DCs). Furthermore, chitin- and IL-33-stimulated DC-derived IL-1β promoted OVA-specific Th2 cell activation, resulting in aggravation of OVA-induced airway inflammation. These findings indicate the adjuvant activity of chitin via a new mechanism and provide important clues for development of therapeutics for allergic disorders caused by HDM, fungi and crustaceans.
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Grants
- Grants-in-Aid for Young Scientists (22790941 and 24791005) and Grants-in-Aid for Scientific Research (26461491) from the Ministry of Education, Culture, Sports, Science and Technology, Japan. The Grant for Joint Research Project of the Institute of Medical Science, the University of Tokyo (2024)
- Grants-in-Aid for Young Scientists (25860822) from the Ministry of Education, Culture, Sports, Science and Technology, Japan
- Grants-in-Aid for Challenging Exploratory Research (15K15377 and 16K15515) from the Ministry of Education, Culture, Sports, Science and Technology, Japan.A Health Labour Sciences Research Grant from the Ministry of Health, Labour and Welfare, Japan.
- Grants-in-Aid for Young Scientists (21790942 and 24688029) and the Program for Improvement of Research Environment for Young Researchers, The Special Coordination Funds for Promoting Science and Technology from the Ministry of Education, Culture, Sports, Science and Technology, Japan. Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency. A Health Labour Sciences Research Grant from the Ministry of Health, Labour and Welfare, Japan
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Affiliation(s)
- Ken Arae
- Department of Immunology, Faculty of Health Sciences, Kyorin University, Tokyo, 181-8612, Japan
- Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, Tokyo, 157-8535, Japan
| | - Hideaki Morita
- Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, Tokyo, 157-8535, Japan
| | - Hirotoshi Unno
- Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, Tokyo, 157-8535, Japan
| | - Kenichiro Motomura
- Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, Tokyo, 157-8535, Japan
| | - Sumika Toyama
- Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, Tokyo, 157-8535, Japan
| | - Naoko Okada
- Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, Tokyo, 157-8535, Japan
| | - Tatsukuni Ohno
- Department of Molecular Immunology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, 113-8510, Japan
| | - Masato Tamari
- Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, Tokyo, 157-8535, Japan
| | - Keisuke Orimo
- Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, Tokyo, 157-8535, Japan
| | - Yuko Mishima
- Department of Immunology, Faculty of Health Sciences, Kyorin University, Tokyo, 181-8612, Japan
| | - Hajime Suto
- Atopy Research Center, Juntendo University, Tokyo, 113-0033, Japan
| | - Ko Okumura
- Atopy Research Center, Juntendo University, Tokyo, 113-0033, Japan
| | - Katsuko Sudo
- Animal Research Center, Tokyo Medical University, Tokyo, 160-8402, Japan
| | - Hiroshi Miyazawa
- Department of Medical technology, Faculty of Health Sciences, Kyorin University, Tokyo, 181-8612, Japan
| | - Haruhiko Taguchi
- Department of Immunology, Faculty of Health Sciences, Kyorin University, Tokyo, 181-8612, Japan
| | - Hirohisa Saito
- Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, Tokyo, 157-8535, Japan
| | - Kenji Matsumoto
- Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, Tokyo, 157-8535, Japan
| | - Susumu Nakae
- Laboratory of Systems Biology, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan.
- Precursory Research for Embryonic Science and Technology (PREST), Japan Science and Technology Agency, Saitama, Japan.
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Affiliation(s)
- Giovanna Traina
- Department of Pharmaceutical Sciences, University of Perugia, Via S. Costanzo, 06126 Perugia, Italy. Tel.: ; Fax: ; E-mail:
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38
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McKnight CG, Jude JA, Zhu Z, Panettieri RA, Finkelman FD. House Dust Mite-Induced Allergic Airway Disease Is Independent of IgE and FcεRIα. Am J Respir Cell Mol Biol 2017; 57:674-682. [PMID: 28700253 DOI: 10.1165/rcmb.2016-0356oc] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
IgE contributes to disease exacerbations but not to baseline airway hyperresponsiveness (AHR) in human asthma. In rodent allergic airway disease (AAD), mast cell and IgE dependence for the induction of AHR has only been observed when mice are immunized with a relatively weak allergen without adjuvant. To evaluate the role of IgE in murine AAD that is induced by a potent allergen, we inoculated BALB/c and FVB/N background wild-type and IgE- or FcεRIα-deficient mice intratracheally with large or limiting doses of house dust mite extract (HDM) and evaluated AHR, pulmonary eosinophilia, goblet cell metaplasia, serum IgE, and lung mastocytosis. We found that neither IgE nor FcεRIα contributed to AAD, even in mice inoculated with the lowest dose of HDM, which readily induced detectable disease, but did not increase serum IgE or pulmonary mast cell levels. In contrast, high doses of HDM strikingly increased serum IgE and pulmonary mast cells, although both AHR and airway mast cell degranulation were equally elevated in wild-type and IgE-deficient mice. Surprisingly, allergen challenge of mice with severe AAD and pulmonary mastocytosis failed to acutely increase airway resistance, lung Newtonian resistance, or hysteresis. Overall, this study shows that, although mice may not reliably model acute asthma exacerbations, mechanisms that are IgE and FcεRIα independent are responsible for AHR and airway inflammation when low doses of a potent allergen are inhaled repetitively.
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Affiliation(s)
- Christopher G McKnight
- 1 Department of Immunology, Allergy and Rheumatology, University of Cincinnati, Cincinnati, Ohio.,2 Medical Service, Cincinnati Veterans Affairs Medical Center, Cincinnati, Ohio
| | - Joseph A Jude
- 3 Rutgers Institute for Translational Medicine and Science, New Brunswick, New Jersey.,4 Child Health Institute of New Jersey, Rutgers, State University of New Jersey, New Brunswick, New Jersey
| | - Zhenqi Zhu
- 1 Department of Immunology, Allergy and Rheumatology, University of Cincinnati, Cincinnati, Ohio
| | - Reynold A Panettieri
- 4 Child Health Institute of New Jersey, Rutgers, State University of New Jersey, New Brunswick, New Jersey.,5 Rutgers Robert Wood Johnson Medical School, Medicine, Piscataway, New Jersey; and
| | - Fred D Finkelman
- 1 Department of Immunology, Allergy and Rheumatology, University of Cincinnati, Cincinnati, Ohio.,2 Medical Service, Cincinnati Veterans Affairs Medical Center, Cincinnati, Ohio.,6 Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
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Cho M, Lee JE, Lim H, Shin HW, Khalmuratova R, Choi G, Kim HS, Choi WS, Park YJ, Shim I, Kim BS, Kang CY, Kim JO, Tanaka S, Kubo M, Tung HY, Landers CT, Corry DB, Kheradmand F, Chung Y. Fibrinogen cleavage products and Toll-like receptor 4 promote the generation of programmed cell death 1 ligand 2-positive dendritic cells in allergic asthma. J Allergy Clin Immunol 2017; 142:530-541.e6. [PMID: 29038008 DOI: 10.1016/j.jaci.2017.09.019] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2017] [Revised: 08/23/2017] [Accepted: 09/22/2017] [Indexed: 10/18/2022]
Abstract
BACKGROUND Inhaled protease allergens preferentially trigger TH2-mediated inflammation in allergic asthma. The role of dendritic cells (DCs) on induction of TH2 cell responses in allergic asthma has been well documented; however, the mechanism by which protease allergens induce TH2-favorable DCs in the airway remains unclear. OBJECTIVE We sought to determine a subset of DCs responsible for TH2 cell responses in allergic asthma and the mechanism by which protease allergens induce the DC subset in the airway. METHODS Mice were challenged intranasally with protease allergens or fibrinogen cleavage products (FCPs) to induce allergic airway inflammation. DCs isolated from mediastinal lymph nodes were analyzed for surface phenotype and T-cell stimulatory function. Anti-Thy1.2 and Mas-TRECK mice were used to deplete innate lymphoid cells and mast cells, respectively. Adoptive cell transfer, bone marrow DC culture, anti-IL-13, and Toll-like receptor (TLR) 4-deficient mice were used for further mechanistic studies. RESULTS Protease allergens induced a remarkable accumulation of TH2-favorable programmed cell death 1 ligand 2 (PD-L2)+ DCs in mediastinal lymph nodes, which was significantly abolished in mice depleted of mast cells and, to a lesser extent, innate lymphoid cells. Mechanistically, FCPs generated by protease allergens triggered IL-13 production from wild-type mast cells but not from TLR4-deficient mast cells, which resulted in an increase in the number of PD-L2+ DCs. Intranasal administration of FCPs induced an increase in numbers of PD-L2+ DCs in the airway, which was significantly abolished in TLR4- and mast cell-deficient mice. Injection of IL-13 restored the PD-L2+ DC population in mice lacking mast cells. CONCLUSION Our findings unveil the "protease-FCP-TLR4-mast cell-IL-13" axis as a molecular mechanism for generation of TH2-favorable PD-L2+ DCs in allergic asthma and suggest that targeting the PD-L2+ DC pathway might be effective in suppressing allergic T-cell responses in the airway.
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Affiliation(s)
- Minkyoung Cho
- Laboratory of Immune Regulation, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Korea
| | - Jeong-Eun Lee
- Laboratory of Immune Regulation, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Korea
| | - Hoyong Lim
- Laboratory of Immune Regulation, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Korea
| | - Hyun-Woo Shin
- Department of Pharmacology, College of Medicine, Seoul National University, Seoul, Korea; Department of Biomedical Sciences and Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Seoul, Korea
| | - Roza Khalmuratova
- Department of Pharmacology, College of Medicine, Seoul National University, Seoul, Korea
| | - Garam Choi
- Laboratory of Immune Regulation, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Korea
| | | | | | - Young-Jun Park
- Laboratory of Immune Regulation, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Korea
| | - Inbo Shim
- Laboratory of Immune Regulation, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Korea
| | - Byung-Seok Kim
- Laboratory of Immune Regulation, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Korea
| | - Chang-Yuil Kang
- Laboratory of Immune Regulation, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Korea
| | - Jae-Ouk Kim
- Laboratory Science Division, International Vaccine Institute, Seoul, Korea
| | - Shinya Tanaka
- Research Institute for Biomedical Science, Tokyo University of Science, Tokyo, and the RIKEN Center for Integrative Medical Sciences (IMS), Yokohama, Japan
| | - Masato Kubo
- Research Institute for Biomedical Science, Tokyo University of Science, Tokyo, and the RIKEN Center for Integrative Medical Sciences (IMS), Yokohama, Japan
| | - Hui-Ying Tung
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, Tex
| | - Cameron T Landers
- Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, Tex
| | - David B Corry
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, Tex; Department of Medicine, Baylor College of Medicine, Houston, Tex; Biology of Inflammation Center, Baylor College of Medicine, Houston, Tex
| | - Farrah Kheradmand
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, Tex; Department of Medicine, Baylor College of Medicine, Houston, Tex; Biology of Inflammation Center, Baylor College of Medicine, Houston, Tex
| | - Yeonseok Chung
- Laboratory of Immune Regulation, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Korea.
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Increased mast cell degranulation and co-localization of mast cells with the NMDA receptor-1 during healing after Achilles tendon rupture. Cell Tissue Res 2017; 370:451-460. [PMID: 28975451 DOI: 10.1007/s00441-017-2684-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Accepted: 08/23/2017] [Indexed: 10/18/2022]
Abstract
The role of inflammation and the mechanism of tendon healing after rupture has historically been a matter of controversy. The purpose of the present study is to investigate the role of mast cells and their relation to the NMDA receptor-1 (a glutamate receptor) during healing after Achilles tendon rupture. Eight female Sprague Dawley rats had their right Achilles tendon transected. Three weeks after rupture, histological quantification of mast cell numbers and their state of degranulation was assessed by histochemistry. Co-localization of mast cell tryptase (a mast cell marker) and NMDA receptor-1 was determined by immunofluorescence. The intact left Achilles tendon was used as control. An increased number of mast cells and a higher proportion of degranulated mast cells were found in the healing Achilles tendon compared to the intact. In addition, increased co-localization of mast cell tryptase and NMDA receptor-1 was seen in the areas of myotendinous junction, mid-tendon proper and bone tendon junction of the healing versus the intact tendon. These findings introduce a possible role for mast cells in the healing phase after Achilles tendon rupture.
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Oettgen HC. Fifty years later: Emerging functions of IgE antibodies in host defense, immune regulation, and allergic diseases. J Allergy Clin Immunol 2017; 137:1631-1645. [PMID: 27263999 DOI: 10.1016/j.jaci.2016.04.009] [Citation(s) in RCA: 68] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2016] [Revised: 04/22/2016] [Accepted: 04/22/2016] [Indexed: 01/15/2023]
Abstract
Fifty years ago, after a long search, IgE emerged as the circulating factor responsible for triggering allergic reactions. Its extremely low concentration in plasma created significant hurdles for scientists working to reveal its identity. We now know that IgE levels are invariably increased in patients affected by atopic conditions and that IgE provides the critical link between the antigen recognition role of the adaptive immune system and the effector functions of mast cells and basophils at mucosal and cutaneous sites of environmental exposure. This review discusses the established mechanisms of action of IgE in pathologic immediate hypersensitivity, as well as its multifaceted roles in protective immunity, control of mast cell homeostasis, and its more recently revealed immunomodulatory functions.
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Affiliation(s)
- Hans C Oettgen
- Division of Immunology, Boston Children's Hospital, and the Department of Pediatrics, Harvard Medical School, Boston, Mass.
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Lin RL, Gu Q, Lee LY. Hypersensitivity of Vagal Pulmonary Afferents Induced by Tumor Necrosis Factor Alpha in Mice. Front Physiol 2017; 8:411. [PMID: 28659824 PMCID: PMC5470033 DOI: 10.3389/fphys.2017.00411] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2017] [Accepted: 05/30/2017] [Indexed: 12/31/2022] Open
Abstract
Tumor necrosis factor alpha (TNFα), a pro-inflammatory cytokine, plays a significant role in the pathogenesis of allergic asthma. Inhalation of TNFα also induces airway hyperresponsiveness in healthy human subjects, and the underlying mechanism is not fully understood. A recent study reported that TNFα caused airway inflammation and a sustained elevation of pulmonary chemoreflex responses in mice, suggesting a possible involvement of heightened sensitivity of vagal pulmonary C-fibers. To investigate this possibility, the present study aimed to investigate the effect of a pretreatment with TNFα on the sensitivity of vagal pulmonary afferents in anesthetized mice. After TNFα (10 μg/ml, 0.03 ml) and vehicle (Veh; phosphate buffered saline (PBS), 0.03 ml) were administered by intra-tracheal instillation in each mouse of treated (TNF) and control (Veh) groups, respectively, the peak activity of pulmonary C-fibers in response to an intravenous bolus injection of a low dose of capsaicin (Cap; 0.5 μg/kg) was significantly elevated in TNF group (6.5 ± 1.3 impulses/s, n = 12) 24–48 h later, compared to that in Veh group (2.2 ± 0.5 impulses/s, n = 11; P < 0.05). Interestingly, the same low dose of Cap injection also evoked a distinct burst of discharge (2.4 ± 0.7 impulses/s) in 75% of the silent rapidly adapting receptors (RARs), a subtype of RARs exhibiting no phasic activity, in TNF group, but did not stimulate any of the silent RARs in Veh group. To further determine if this sensitizing effect involves a direct action of TNFα on these sensory nerves, the change in intracellular Ca2+ concentration in response to Cap challenge was measured in isolated mouse vagal pulmonary sensory neurons. The Cap-evoked Ca2+ influx was markedly enhanced in the neurons incubated with TNFα (50 ng/ml) for ~24 h, and this sensitizing effect was attenuated in the neurons isolated from the TNF-receptor double homozygous mutant mice. In conclusion, the TNFα pretreatment enhanced the Cap sensitivity in both pulmonary C-fibers and silent RARs, and the action was mediated through TNF receptors. These sensitizing effects of TNFα may contribute, at least in part, to the pathogenesis of airway hyperresponsiveness induced by this cytokine.
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Affiliation(s)
- Ruei-Lung Lin
- Department of Physiology, University of Kentucky, Lexington, KY, United States
| | - Qihai Gu
- Department of Biomedical Sciences, Mercer University, Macon, GA, United States
| | - Lu-Yuan Lee
- Department of Physiology, University of Kentucky, Lexington, KY, United States
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Lin RL, Gu Q, Khosravi M, Lee LY. Sustained sensitizing effects of tumor necrosis factor alpha on sensory nerves in lung and airways. Pulm Pharmacol Ther 2017; 47:29-37. [PMID: 28587842 DOI: 10.1016/j.pupt.2017.06.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2017] [Revised: 05/30/2017] [Accepted: 06/03/2017] [Indexed: 01/07/2023]
Abstract
Tumor necrosis factor alpha (TNFα) plays a significant role in the pathogenesis of airway inflammatory diseases. Inhalation of aerosolized TNFα induced airway hyperresponsiveness accompanied by airway inflammation in healthy human subjects, but the underlying mechanism is not fully understood. We recently reported a series of studies aimed to investigate if TNFα elevates the sensitivity of vagal bronchopulmonary sensory nerves in a mouse model; these studies are summarized in this mini-review. Our results showed that intratracheal instillation of TNFα induced pronounced airway inflammation 24 h later, as illustrated by infiltration of eosinophils and neutrophils and the release of inflammatory mediators and cytokines in the lung and airways. Accompanying these inflammatory reactions, the sensitivity of vagal pulmonary C-fibers and silent rapidly adapting receptors to capsaicin, a selective agonist of transient receptor potential vanilloid type 1 receptor, was markedly elevated after the TNFα treatment. A distinct increase in the sensitivity to capsaicin induced by TNFα was also observed in isolated pulmonary sensory neurons, suggesting that the sensitizing effect is mediated primarily through a direct action of TNFα on these neurons. Furthermore, the same TNFα treatment also induced a lingering (>7days) cough hyperresponsiveness to inhalation challenge of NH3 in awake mice. Both the airway inflammation and the sensitizing effect on pulmonary sensory neurons caused by the TNFα treatment were abolished in the TNF-receptor double homozygous mutant mice, indicating the involvement of TNF-receptor activation. These findings suggest that the TNFα-induced hypersensitivity of vagal bronchopulmonary afferents may be responsible for, at least in part, the airway hyperresponsiveness caused by inhaled TNFα in healthy individuals.
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Affiliation(s)
- Ruei-Lung Lin
- Department of Physiology, University of Kentucky, Lexington, KY, USA
| | - Qihai Gu
- Department of Biomedical Sciences, Mercer University, Macon, GA, USA
| | - Mehdi Khosravi
- Department of Medicine, University of Kentucky, Lexington, KY, USA
| | - Lu-Yuan Lee
- Department of Physiology, University of Kentucky, Lexington, KY, USA.
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Burton OT, Tamayo JM, Stranks AJ, Koleoglou KJ, Oettgen HC. Allergen-specific IgG antibody signaling through FcγRIIb promotes food tolerance. J Allergy Clin Immunol 2017; 141:189-201.e3. [PMID: 28479335 DOI: 10.1016/j.jaci.2017.03.045] [Citation(s) in RCA: 62] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2016] [Revised: 03/20/2017] [Accepted: 03/27/2017] [Indexed: 12/27/2022]
Abstract
BACKGROUND Patients with food allergy produce high-titer IgE antibodies that bind to mast cells through FcεRI and trigger immediate hypersensitivity reactions on antigen encounter. Food-specific IgG antibodies arise in the setting of naturally resolving food allergy and accompany the acquisition of food allergen unresponsiveness in oral immunotherapy. OBJECTIVE In this study we sought to delineate the effects of IgG and its inhibitory Fc receptor, FcγRIIb, on both de novo allergen sensitization in naive animals and on established immune responses in the setting of pre-existing food allergy. METHODS Allergen-specific IgG was administered to mice undergoing sensitization and desensitization to the model food allergen ovalbumin. Cellular and molecular mechanisms were interrogated by using mast cell- and FcγRIIb-deficient mice. The requirement for FcγRII in IgG-mediated inhibition of human mast cells was investigated by using a neutralizing antibody. RESULTS Administration of specific IgG to food allergy-prone IL4raF709 mice during initial food exposure prevented the development of IgE antibodies, TH2 responses, and anaphylactic responses on challenge. When given as an adjunct to oral desensitization in mice with established IgE-mediated hypersensitivity, IgG facilitated tolerance restoration, favoring expansion of forkhead box protein 3-positive regulatory T cells along with suppression of existing TH2 and IgE responses. IgG and FcγRIIb suppress adaptive allergic responses through effects on mast cell function. CONCLUSION These findings suggest that allergen-specific IgG antibodies can act to induce and sustain immunologic tolerance to foods.
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Affiliation(s)
- Oliver T Burton
- Department of Medicine, Boston Children's Hospital, Boston, Mass; Department of Pediatrics, Harvard Medical School, Boston, Mass.
| | - Jaciel M Tamayo
- Department of Medicine, Boston Children's Hospital, Boston, Mass; Department of Pediatrics, Harvard Medical School, Boston, Mass
| | - Amanda J Stranks
- Department of Medicine, Boston Children's Hospital, Boston, Mass; Department of Pediatrics, Harvard Medical School, Boston, Mass
| | - Kyle J Koleoglou
- Department of Medicine, Boston Children's Hospital, Boston, Mass
| | - Hans C Oettgen
- Department of Medicine, Boston Children's Hospital, Boston, Mass; Department of Pediatrics, Harvard Medical School, Boston, Mass
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Balbino B, Sibilano R, Starkl P, Marichal T, Gaudenzio N, Karasuyama H, Bruhns P, Tsai M, Reber LL, Galli SJ. Pathways of immediate hypothermia and leukocyte infiltration in an adjuvant-free mouse model of anaphylaxis. J Allergy Clin Immunol 2017; 139:584-596.e10. [PMID: 27555460 PMCID: PMC5241268 DOI: 10.1016/j.jaci.2016.05.047] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2015] [Revised: 05/16/2016] [Accepted: 05/31/2016] [Indexed: 01/07/2023]
Abstract
BACKGROUND Conflicting results have been obtained regarding the roles of Fc receptors and effector cells in models of active systemic anaphylaxis (ASA). In part, this might reflect the choice of adjuvant used during sensitization because various adjuvants might differentially influence the production of particular antibody isotypes. OBJECTIVE We developed an "adjuvant-free" mouse model of ASA and assessed the contributions of components of the "classical" and "alternative" pathways in this model. METHODS Mice were sensitized intraperitoneally with ovalbumin at weekly intervals for 6 weeks and challenged intraperitoneally with ovalbumin 2 weeks later. RESULTS Wild-type animals had immediate hypothermia and late-phase intraperitoneal inflammation in this model. These features were reduced in mice lacking the IgE receptor FcεRI, the IgG receptor FcγRIII or the common γ-chain FcRγ. FcγRIV blockade resulted in a partial reduction of inflammation without any effect on hypothermia. Depletion of monocytes/macrophages with clodronate liposomes significantly reduced the hypothermia response. By contrast, depletion of neutrophils or basophils had no significant effects in this ASA model. Both the hypothermia and inflammation were dependent on platelet-activating factor and histamine and were reduced in 2 types of mast cell (MC)-deficient mice. Finally, engraftment of MC-deficient mice with bone marrow-derived cultured MCs significantly exacerbated the hypothermia response and restored inflammation to levels similar to those observed in wild-type mice. CONCLUSION Components of the classical and alternative pathways contribute to anaphylaxis in this adjuvant-free model, with key roles for MCs and monocytes/macrophages.
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MESH Headings
- Adjuvants, Immunologic
- Anaphylaxis/immunology
- Animals
- Cell Movement
- Cells, Cultured
- Complement Pathway, Alternative
- Complement Pathway, Classical
- Disease Models, Animal
- Humans
- Hypothermia/immunology
- Immunization
- Leukocytes/immunology
- Macrophages/immunology
- Mast Cells/immunology
- Mast Cells/transplantation
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Receptors, IgE/genetics
- Receptors, IgE/metabolism
- Receptors, IgG/genetics
- Receptors, IgG/metabolism
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Affiliation(s)
- Bianca Balbino
- Institut Pasteur, Department of Immunology, Unit of Antibodies in Therapy and Pathology, Paris, France; INSERM, U1222, Paris, France; Université Pierre et Marie Curie, Paris, France
| | - Riccardo Sibilano
- Department of Pathology, Stanford University School of Medicine, Stanford, Calif; Sean N. Parker Center for Allergy and Asthma Research, Stanford University School of Medicine, Stanford, Calif
| | - Philipp Starkl
- Department of Pathology, Stanford University School of Medicine, Stanford, Calif; Sean N. Parker Center for Allergy and Asthma Research, Stanford University School of Medicine, Stanford, Calif
| | - Thomas Marichal
- Department of Pathology, Stanford University School of Medicine, Stanford, Calif
| | - Nicolas Gaudenzio
- Department of Pathology, Stanford University School of Medicine, Stanford, Calif; Sean N. Parker Center for Allergy and Asthma Research, Stanford University School of Medicine, Stanford, Calif
| | - Hajime Karasuyama
- Department of Immune Regulation, Tokyo Medical and Dental University, Graduate School of Medical and Dental Sciences, Tokyo, Japan
| | - Pierre Bruhns
- Institut Pasteur, Department of Immunology, Unit of Antibodies in Therapy and Pathology, Paris, France; INSERM, U1222, Paris, France
| | - Mindy Tsai
- Department of Pathology, Stanford University School of Medicine, Stanford, Calif; Sean N. Parker Center for Allergy and Asthma Research, Stanford University School of Medicine, Stanford, Calif
| | - Laurent L Reber
- Institut Pasteur, Department of Immunology, Unit of Antibodies in Therapy and Pathology, Paris, France; INSERM, U1222, Paris, France; Department of Pathology, Stanford University School of Medicine, Stanford, Calif; Sean N. Parker Center for Allergy and Asthma Research, Stanford University School of Medicine, Stanford, Calif.
| | - Stephen J Galli
- Department of Pathology, Stanford University School of Medicine, Stanford, Calif; Sean N. Parker Center for Allergy and Asthma Research, Stanford University School of Medicine, Stanford, Calif; Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, Calif.
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Yu G, Zhang Y, Ren W, Dong L, Li J, Geng Y, Zhang Y, Li D, Xu H, Yang H. Network pharmacology-based identification of key pharmacological pathways of Yin-Huang-Qing-Fei capsule acting on chronic bronchitis. Int J Chron Obstruct Pulmon Dis 2016; 12:85-94. [PMID: 28053519 PMCID: PMC5191847 DOI: 10.2147/copd.s121079] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
For decades in China, the Yin-Huang-Qing-Fei capsule (YHQFC) has been widely used in the treatment of chronic bronchitis, with good curative effects. Owing to the complexity of traditional Chinese herbal formulas, the pharmacological mechanism of YHQFC remains unclear. To address this problem, a network pharmacology-based strategy was proposed in this study. At first, the putative target profile of YHQFC was predicted using MedChem Studio, based on structural and functional similarities of all available YHQFC components to the known drugs obtained from the DrugBank database. Then, an interaction network was constructed using links between putative YHQFC targets and known therapeutic targets of chronic bronchitis. Following the calculation of four topological features (degree, betweenness, closeness, and coreness) of each node in the network, 475 major putative targets of YHQFC and their topological importance were identified. In addition, a pathway enrichment analysis based on the Kyoto Encyclopedia of Genes and Genomes pathway database indicated that the major putative targets of YHQFC are significantly associated with various pathways involved in anti-inflammation processes, immune responses, and pathological changes caused by asthma. More interestingly, eight major putative targets of YHQFC (interleukin [IL]-3, IL-4, IL-5, IL-10, IL-13, FCER1G, CCL11, and EPX) were demonstrated to be associated with the inflammatory process that occurs during the progression of asthma. Finally, a molecular docking simulation was performed and the results exhibited that 17 pairs of chemical components and candidate YHQFC targets involved in asthma pathway had strong binding efficiencies. In conclusion, this network pharmacology-based investigation revealed that YHQFC may attenuate the inflammatory reaction of chronic bronchitis by regulating its candidate targets, which may be implicated in the major pathological processes of the asthma pathway.
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Affiliation(s)
- Guohua Yu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing
| | - Yanqiong Zhang
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing
| | - Weiqiong Ren
- The First Affiliated Hospital of Hunan University of Traditional Chinese Medicine, Changsha
| | - Ling Dong
- School of Chinese Materia Medica, Beijing University of Chinese Medicine
| | - Junfang Li
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin
| | - Ya Geng
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing
- School of Basic Medicine, Shandong University of Chinese Medicine, Jinan, China
| | - Yi Zhang
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing
| | - Defeng Li
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing
| | - Haiyu Xu
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing
| | - Hongjun Yang
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing
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Arora P, Ansari SH, Najmi AK, Anjum V, Ahmad S. Investigation of anti-asthmatic potential of dried fruits of Vitis vinifera L. in animal model of bronchial asthma. Allergy Asthma Clin Immunol 2016; 12:42. [PMID: 27536321 PMCID: PMC4988050 DOI: 10.1186/s13223-016-0145-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Accepted: 07/21/2016] [Indexed: 12/28/2022] Open
Abstract
Background Fruits of Vitis vinifera L., commonly known as grapes, are largely consumed worldwide because of their high nutritional and medicinal benefits. Context and purpose The present study investigated effects of V. vinifera fruits in ovalbumin-induced animal model of bronchial asthma. Methods Male wistar rats (except group 1) were sensitized with allergen (ovalbumin, 40 mg/rat + aluminum hydroxide, 2 mg/rat). Groups of sensitized animals were treated orally with either vehicle (0.4 mL/kg), standard dexamethasone (2.5 mg/kg) or alcoholic extract of V. vinifera dried fruits (31 and 42.5 mg/kg) from day 1 to 28 (n = 6 for all groups). Inflammatory markers including cell counts, cytokines such as interleukin (IL)-4, IL-5, IL-1β, tumor necrosis factor, immunoglobulin E (IgE), leukotrienes and nitrite levels in both blood/serum and bronchoalveolar fluid were analysed. Breathing rate and tidal volume as lung function parameters were examined by spirometer. Lung tissues were studied for histamine content and histopathology. Results Treatment of sensitized animals with dexamethasone or two doses of V. vinifera fruits extract inhibited recruitment of inflammatory cytokines, IgE, nitrites and circulating cells particularly eosinophils in blood/serum and bronchoalveolar fluid (p < 0.001, p < 0.01 and p < 0.05). Dexamethasone and V. vinifera fruits extract treatment also normalized lung functions and histamine levels compared to ovalbumin-sensitized controls (p < 0.05 and p < 0.01). Moreover, both drugs exhibited protection against airway inflammation in lung histology. Conclusion Results of study demonstrate the effectiveness of V. vinifera fruits in allergic asthma possibly related to its ability to inhibit cellular response and subsequent production of inflammatory cytokines. Electronic supplementary material The online version of this article (doi:10.1186/s13223-016-0145-x) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Poonam Arora
- Department of Pharmacognosy and Phytochemistry, Faculty of Pharmacy, Jamia Hamdard (Hamdard University), New Delhi, 110062 India
| | - S H Ansari
- Department of Pharmacognosy and Phytochemistry, Faculty of Pharmacy, Jamia Hamdard (Hamdard University), New Delhi, 110062 India
| | - Abul Kalam Najmi
- Department of Pharmacology, Faculty of Pharmacy, Jamia Hamdard (Hamdard University), New Delhi, 110062 India
| | - Varisha Anjum
- Department of Pharmacognosy and Phytochemistry, Faculty of Pharmacy, Jamia Hamdard (Hamdard University), New Delhi, 110062 India
| | - Sayeed Ahmad
- Department of Pharmacognosy and Phytochemistry, Faculty of Pharmacy, Jamia Hamdard (Hamdard University), New Delhi, 110062 India
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Serra-Pages M, Torres R, Plaza J, Herrerias A, Costa-Farré C, Marco A, Jiménez M, Maurer M, Picado C, de Mora F. Activation of the Prostaglandin E2 receptor EP2 prevents house dust mite-induced airway hyperresponsiveness and inflammation by restraining mast cells' activity. Clin Exp Allergy 2016; 45:1590-600. [PMID: 25823713 DOI: 10.1111/cea.12542] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2014] [Revised: 03/02/2015] [Accepted: 03/03/2015] [Indexed: 01/31/2023]
Abstract
BACKGROUND Prostaglandin E2 (PGE2 ) has been proposed to exert antiasthmatic effects in patients, to prevent antigen-induced airway pathology in murine models, and to inhibit mast cells (MC) activity in vitro. OBJECTIVE To assess in a murine model whether the protective effect of PGE2 may be a consequence of its ability to activate the E-prostanoid (EP)2 receptor on airway MC. METHODS Either BALB/c or C57BL/6 mice were exposed intranasally (i.n.) to house dust mite (HDM) aeroallergens. Both strains were given PGE2 locally (0.3 mg/kg), but only BALB/c mice were administered butaprost (EP2 agonist: 0.3 mg/kg), or AH6809 (EP2 antagonist; 2.5 mg/kg) combined with the MC stabilizer sodium cromoglycate (SCG: 25 mg/kg). Airway hyperresponsiveness (AHR) and inflammation, along with lung MC activity, were evaluated. In addition, butaprost's effect was assessed in MC-mediated passive cutaneous anaphylaxis (PCA) in mice challenged with 2,4-dinitrophenol (DNP). RESULTS Selective EP2 agonism attenuated aeroallergen-caused AHR and inflammation in HDM-exposed BALB/c mice, and this correlated with a reduced lung MC activity. Accordingly, the blockade of endogenous PGE2 by means of AH6809 worsened airway responsiveness in sensitive BALB/c mice, and such worsening was reversed by SCG. The relevance of MC to PGE2 -EP2 driven protection was further highlighted in MC-dependent PCA, where butaprost fully prevented MC-induced ear swelling. Unlike in BALB/c mice, PGE2 did not protect the airways of HDM-sensitized C57BL/6 animals, a strain in which we showed MC to be irrelevant to aeroallergen-driven AHR and inflammation. CONCLUSIONS & CLINICAL RELEVANCE The beneficial effect of both exogenous and endogenous PGE2 in aeroallergen-sensitized mice may be attributable to the activation of the EP2 receptor, which in turn acts as a restrainer of airway MC activity. This opens a path towards the identification of therapeutic targets against asthma along the 'EP2 -MC-airway' axis.
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Affiliation(s)
- M Serra-Pages
- Department of Pharmacology, Therapeutics and Toxicology, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - R Torres
- Department of Pharmacology, Therapeutics and Toxicology, Universitat Autònoma de Barcelona, Barcelona, Spain.,CIBER (Centro de Investigación Biomédica en Red) de Enfermedades Respiratorias, Barcelona, Spain.,Department of Cellular Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - J Plaza
- Department of Pharmacology, Therapeutics and Toxicology, Universitat Autònoma de Barcelona, Barcelona, Spain.,CIBER (Centro de Investigación Biomédica en Red) de Enfermedades Respiratorias, Barcelona, Spain
| | - A Herrerias
- Department of Pharmacology, Therapeutics and Toxicology, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - C Costa-Farré
- Department of Surgery and Animals Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - A Marco
- Department of Surgery and Animals Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - M Jiménez
- Department of Cellular Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Barcelona, Spain.,CIBER (Centro de Investigación Biomédica en Red) de Enfermedades Hepáticas y Digestivas
| | - M Maurer
- Department of Dermatology, Charité -Universitätsmedizin Berlin, Berlin, Germany
| | - C Picado
- CIBER (Centro de Investigación Biomédica en Red) de Enfermedades Respiratorias, Barcelona, Spain.,Department of Pneumology and Respiratory Allergy, Hospital Clínic, IDIBAPS (Institut d'Investigacions Biomèdiques August Pi i Sunyer), Universitat de Barcelona, Barcelona, Spain
| | - F de Mora
- Department of Pharmacology, Therapeutics and Toxicology, Universitat Autònoma de Barcelona, Barcelona, Spain
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Adenoviral delivery of recombinant soluble human tumor necrosis factor receptor 1 partially normalized mouse model of asthma. J Investig Med 2016; 63:765-72. [PMID: 25923882 DOI: 10.1097/jim.0000000000000200] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Tumor necrosis factor α (TNF-α) is a proinflammatory cytokine that has been implicated in the airway pathology of asthma and result in resistance to hormone therapy. Tumor necrosis factor α inhibitors have become a major research focus in the treatment of asthma. METHODS Recombinant adenovirus (Ad-sTNFR1-IgGFc) expressing a fusion protein (sTNFR1-IgGFc), which was consisted of the soluble extracellular region of TNF receptor 1 and Fc fragment of IgG (sTNFR1-IgGFc), was used to transduce primary human airway smooth muscle cells (HASMCs). Enzyme-linked immunosorbent assay, flow cytometry, and immunocytochemistry confirmed the expression of sTNFR1-IgGFc. MTT was used to test the effect of sTNFR1-IgGFc to antagonism TNF-α-induced proliferates of HASMCs. To investigate the in vivo effectiveness of sTNFR1-IgGFc, mouse model of asthma was established. Ad-sTNFR1-IgGFc was delivered to the lung via nasal spray. Expression of sTNFR1-IgGFc in the tissue was confirmed by in situ hybridization and immunohistochemistry. The 2 major cell types that are involved in the inflamed asthmatic airway, neutrophils and eosinophils, in bronchoalveolar lavage fluid were observed. RESULTS The sTNFR1-IgGFc isolated from transduced HASMC culture supernatant was able to antagonize HASMC proliferation stimulated by TNF-α. Asthma-induced pathologies and alterations in the cell composition in bronchoalveolar lavage fluid were reduced in mice subjected to Ad-sTNFR1-IgGFc therapy. CONCLUSIONS The soluble extracellular region of TNF receptor 1 and Fc fragment of IgG was able to functionally antagonize TNF-α in vitro and showed promise as a therapeutic agent for the localized treatment of severe refractory asthma.
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Somineni HK, Zhang X, Biagini Myers JM, Kovacic MB, Ulm A, Jurcak N, Ryan PH, Khurana Hershey GK, Ji H. Ten-eleven translocation 1 (TET1) methylation is associated with childhood asthma and traffic-related air pollution. J Allergy Clin Immunol 2016; 137:797-805.e5. [PMID: 26684294 PMCID: PMC4783231 DOI: 10.1016/j.jaci.2015.10.021] [Citation(s) in RCA: 104] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2015] [Revised: 10/05/2015] [Accepted: 10/13/2015] [Indexed: 11/24/2022]
Abstract
BACKGROUND Asthma is a complex disorder influenced by genetics and the environment. Recent findings have linked abnormal DNA methylation in T cells with asthma; however, the potential dysregulation of methylation in airway epithelial cells is unknown. Studies of mouse models of asthma have observed greater levels of 5-hydroxymethylcytosine (5-hmC) and ten-eleven translocation 1 (TET1) expression in lungs. TET proteins are known to catalyze methylation through modification of 5-methylcytosine to 5-hmC. OBJECTIVE We sought to examine the association of TET1 methylation with asthma and traffic-related air pollution (TRAP). METHODS TET1 methylation levels from DNA derived from nasal airway epithelial cells collected from 12 African American children with physician-diagnosed asthma and their nonasthmatic siblings were measured by using Illumina 450K arrays. Regions of interest were verified by means of locus-specific pyrosequencing in 35 sibling pairs and replicated in an independent population (n = 186). Exposure to TRAP in participants' early life and at current home addresses was estimated by using a land-use regression model. Methylation studies in saliva, PBMCs, and human bronchial epithelial cells were done to support our findings. RESULTS Loss of methylation at a single CpG site in the TET1 promoter (cg23602092) and increased global 5-hmC levels were significantly associated with asthma. In contrast, TRAP exposure at participants' current homes significantly increased methylation at the same site. Patterns were consistent across tissue sample types. 5-Aza-2'-deoxycytidine and diesel exhaust particle exposure in human bronchial epithelial cells was associated with altered TET1 methylation and expression and global 5-hmC levels. CONCLUSIONS Our findings suggest a possible role of TET1 methylation in asthmatic patients and response to TRAP.
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Affiliation(s)
- Hari K Somineni
- Division of Asthma Research, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Xue Zhang
- Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Jocelyn M Biagini Myers
- Division of Asthma Research, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Melinda Butsch Kovacic
- Division of Asthma Research, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Environmental Health, University of Cincinnati, Cincinnati, Ohio
| | - Ashley Ulm
- Division of Asthma Research, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Noelle Jurcak
- School of Medicine, Johns Hopkins University, Baltimore, Md
| | - Patrick H Ryan
- Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Environmental Health, University of Cincinnati, Cincinnati, Ohio
| | | | - Hong Ji
- Division of Asthma Research, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
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