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Meteorin-β/Meteorin like/IL-41 attenuates airway inflammation in house dust mite-induced allergic asthma

Cellular & Molecular Immunology 2022年第2期19卷 245-259页

作者： Xun Gao Ting-Fan Leung Gary Wing-Kin Wong Wing-Hung Ko Mengyun Cai Ellie Jiayi He Ida Miu-Ting Chu Miranda Sin-Man Tsang Ben Chung-Lap Chan Jiawei Ling Xiao Fan Liwei Lu Christopher Wai-Kei Lam Chun-Kwok Wong Department of Chemical Pathology The Chinese University of Hong KongHong KongChina Department of Paediatrics The Chinese University of Hong KongHong KongChina School of Biomedical Sciences The Chinese University of Hong KongHong KongChina Emory College of Arts and Sciences Emory UniversityAtlantaGAUSA Institute of Chinese Medicine and State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants The Chinese University of Hong KongHong KongChina Department of Pathology and Shenzhen Institute of Research and Innovation The University of Hong KongHong KongChina Faculty of Medicine and State Key Laboratory of Quality Research in Chinese Medicines Macao University of Science and TechnologyMacaoChina Li Dak Sum Yip Yio Chin R&D Centre for Chinese Medicine The Chinese University of Hong KongHong KongChina

We sought to examine the regulatory effect of Meteorin-β(Metrnβ)/Meteorin like(Metrnl)/IL-41 on lung inflammation in allergic asthma.We found that Metrnβwas elevated significantly in asthmatic patients and in mice with allergic asthma induced by house dust mite(HDM)extract.Upon exposure to HDM,Metrnβwas secreted predominantly by airway epithelial cells and inflammatory cells,including macrophages and eosinophils.The increased Metrnβeffectively blocked the development of airway hyperreactivity(AHR)and decreased inflammatory cell airway infiltration and type 2 cytokine production,which was associated with downregulated DC-mediated adaptive immune responses.Moreover,Metrnβimpaired the maturation and function of bone marrow-derived dendritic cells in vitro.asthmatic mice adoptively transferred with dendritic cells isolated from Metrnβ-treated allergic mice displayed decreased AHR,airway inflammation,and lung injury.Metrnβalso displayed anti-inflammatory properties in immunodeficient SCID mice with allergic asthma and in in vitro 3D ALI airway models.Moreover,blockade of Metrnβby anti-Metrnβantibody treatment promoted the development of allergic asthma.These results revealed the unappreciated protective roles of Metrnβin alleviating DC-mediated Th2 inflammation in allergic asthma,providing the novel treatment strategy of therapeutic targeting of Metrnβin allergic asthma.

关键词： Metrnβ Eosinophils Dendritic cells allergic asthma Air-liquid interface

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Anti-inflammatory mechanisms of the novel cytokine interleukin-38 in allergic asthma

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Cellular & Molecular Immunology 2020年第6期17卷 631-646页

作者： Xiaoyu Sun Tianheng Hou Edwin Cheung Tiffany Nga-Teng Iu Victor Wai-Hou Tam Ida Miu-Ting Chu Miranda Sin-Man Tsang Paul Kay-Sheung Chan Christopher Wai-Kei Lam Chun-Kwok Wong Department of Chemical Pathology The Chinese University of Hong KongHong KongChina Cancer Centre/Centre of Precision Medicine Research and Training Faculty of Health SciencesUniversity of MacaoMacaoChina Institute of Chinese Medicine and State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants The Chinese University of Hong KongHong KongChina Department of Microbiology The Chinese University of Hong KongHong KongChina Faculty of Medicine and State Key Laboratory of Quality Research in Chinese Medicines Macao University of Science and TechnologyMacaoChina Li Dak Sum Yip Yio Chin R&D Centre for Chinese Medicine The Chinese University of Hong KongHong KongChina

We elucidated the anti-inflammatory mechanisms of IL-38 in allergic asthma.Human bronchial epithelial cells and eosinophils were cocultured upon stimulation with the viral RLR ligand poly(I:C)/LyoVec or infection-related cytokine TNF-αto induce expression of cytokines/chemokines/adhesion molecules.House dust mite(HDM)-induced allergic asthma and humanized allergic asthma NOD/SCID murine models were established to assess anti-inflammatory mechanisms in vivo.IL-38 significantly inhibited induced proinflammatory IL-6,IL-1β,CCL5,and CXCL10 production,and antiviral interferon-βand intercellular adhesion molecule-1 expression in the coculture system.Mass cytometry and RNA-sequencing analysis revealed that IL-38 could antagonize the activation of the intracellular STAT1,STAT3,p38 MAPK,ERK1/2,and NF-κB pathways,and upregulate the expression of the host defense-related gene POU2AF1 and anti-allergic response gene RGS13.Intraperitoneal injection of IL-38 into HDM-induced allergic asthma mice could ameliorate airway hyperreactivity by decreasing the accumulation of eosinophils in the lungs and inhibiting the expression of the Th2-related cytokines IL-4,IL-5,and IL-13 in the bronchoalveolar lavage fluid(BALF)and lung homogenates.Histological examination indicated lung inflammation was alleviated by reductions in cell infiltration and goblet cell hyperplasia,together with reduced Th2,Th17,and innate lymphoid type 2 cell numbers but increased proportions of regulatory T cells in the lungs,spleen,and lymph nodes.IL-38 administration suppressed airway hyperreactivity and asthma-related IL-4 and IL-5 expression in humanized mice,together with significantly decreased CCR3^(+) eosinophil numbers in the BALF and lungs,and a reduced percentage of human CD4^(+)CRTH2^(+)Th2 cells in the lungs and mediastinal lymph nodes.Together,our results demonstrated the anti-inflammatory mechanisms of IL-38 and provided a basis for the development of a regulatory cytokine-based treatment for allergic asthma.

关键词： allergic asthma eosinophils IL-38 ILC2s Tregs

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Dust mite allergen-specific immunotherapy increases IL4 DNA methylation and induces Der p-specific T cell tolerance in children with allergic asthma

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Cellular & Molecular Immunology 2018年第11期15卷 963-972页

作者： Chuang-Ming Wang Chia-Bin Chang Michael WY Chan Zhi-Hong Wen Shu-Fen Wu Department of Pediatrics Ditmanson Medical Foundation Chia-Yi Christian Hospital60002Chia-YiTaiwanChina Department of Nursing Chang Gung University of Science and Technology61363Chia-YiTaiwanChina Department of Life Science and Institute of Molecular Biology National Chung-Cheng University62102Chia-YiTaiwanChina Department of Marine Biotechnology and Resources Asia-Pacific Ocean Research CenterNational Sun Yat-Sen University80424KaohsiungTaiwanChina

Allergen-specific immunotherapy(allergen-SIT)is a highly effective treatment for children with allergic asthma(AA),an immune-mediated chronic disease leading to bronchial muscle hypertrophy and airway obstruction in response to specific allergens.T helper cells and secreted cytokines play important roles in the pathogenesis of asthma,and epigenetic modulation controls genes important for T cell development and cytokine expression.This study evaluated T helper cell-secreted cytokines and DNA methylation patterns in children treated with Dermatophagoides pteronyssinus(Der p)allergen-SIT.Our results showed that after Der p challenge,peripheral blood mononuclear cells(PBMCs)from the SIT group,compared with the non-SIT AA group,produced lower levels of IL-4,IL-5 and IL-2.The SIT group,compared with the AA group,exhibited decreased sensitivity to the Der p allergen,concurrent with IL-4 down-modulation due to increased promoter DNA methylation,as estimated in PBMCs.Our results showed that SIT decreased IL-4 and IL-5,and inhibited T cell proliferation,by inhibiting IL-2 production after the specific allergen challenge.These results suggest that decreased IL-2 production and increased IL-4 cytokine promoter methylation is a potential mechanism of Der p-specific allergen desensitization immunotherapy.

关键词： allergic asthma allergen-specific immunotherapy dust mite Dermatophagoides pteronyssinus DNA methylation interleukin-4

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Serum macrophage migration inhibitory factor as a potential biomarker to evaluate therapeutic response in patients with allergic asthma:an exploratory study

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2021年第6期22卷 512-520页

作者： Huiyuan ZHU Shaochun YAN Jingshuo WU Zhong ZHANG Xiaolin LI Zheng LIU Xing MA Lina ZHOU Lin ZHANG Mingming FENG Yiwei GENG Aixin ZHANG Sabina JANCIAUSKIENE Aiguo XU Department of Pulmonary and Critical Care Medicine Zhengzhou Second People's HospitalZhengzhou Affiliated Hospital of Jinan UniversityZhengzhou 450006China Department of Pulmonary and Critical Care Medicine First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052China Department of Cell Biology School of Basic and Forensic MedicineBaotou Medical CollegeBaotou 014040China Department of Hematology First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052China Department of Respiratory Medicine German Center for Lung ResearchHannover Medical SchoolHannover 30625Germany

Background:Previous studies have shown that macrophage migration inhibitory factor(MIF)is involved in the pathogenesis of asthma.This study aimed to investigate whether serum MIF reflects a therapeutic response in allergic asthma.Methods:We enrolled 30 asthmatic patients with mild-to-moderate exacerbations and 20 healthy controls,analyzing the parameter levels of serum MIF,serum total immunoglobulin E(tIgE),peripheral blood eosinophil percentage(EOS%),and fractional exhaled nitric oxide(FeNO).Lung function indices were used to identify disease severity and therapeutic response.Results:Our study showed that all measured parameters in patients were at higher levels than those of controls.After one week of treatment,most parameter levels decreased significantly except for serum tIgE.Furthermore,we found that serum MIF positively correlated with EOS%as well as FeNO,but negatively correlated with lung function indices.Receiver operator characteristic(ROC)curve analysis indicated that among the parameters,serum MIF exhibited a higher capacity to evaluate therapeutic response.The area under the curve(AUC)of MIF was 0.931,with a sensitivity of 0.967 and a specificity of 0.800.Conclusions:Our results suggested that serum MIF may serve as a potential biomarker for evaluating therapeutic response in allergic asthma with mild-to-moderate exacerbations.

关键词： Macrophage migration inhibitory factor(MIF) allergic asthma Eosinophilic inflammation Fractional exhaled nitric oxide Immunoglobulin E(IgE)

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Platelets promote allergic asthma through the expression of CD154

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Cellular & Molecular Immunology 2015年第6期12卷 700-707页

作者： Jun Tian Tianyi Zhu Juan Liu Zhenhong Guo Xuetao Cao Institute of Immunology Zhejiang University School of Medicine Hangzhou China National Key Laboratory of Medical Immunology & Institute of Immunology Second Military Medical University Shanghai China Department of Respiration General Hospital of Shenyang Military Region Shenyang China

Platelet activation is associated with multiple immune responses and the pathogenesis of various immune-related diseases. However, the exact role and the underlying mechanism of platelets in the progression of allergic asthma remain largely unclear. In this study, we demonstrate that during antigen sensitization, platelets can be activated by ovalbumin （OVA） aerosol viathe upregulation of CD154 （CD4OL） expression. Platelet transfer promoted allergic asthma progression by inducing more severe leukocyte infiltration and lung inflammation, elevated IgE production and strengthened T helper 2 （Th2） responses in asthma-induced mice. Accordingly, platelet depletion compromised allergic asthma progression. CdI54-deficient platelets failed to promote asthma development, indicating the requirement of CD154 for platelets to promote asthma progression. The mechanistic study showed that platelets inhibited the induction of Foxp3 ＋ regulatory T cells both in vivoand in vitroat least partially through CD154, providing an explanation for the increase of Th2 responses by platelet transfer. Our study reveals the previously unknown role of platelet CD154 in the promotion of asthma progression by polarizing Th2 responses and inhibiting regulatory T-cell generation and thus provides a potential clue for allergic disease interventions.

关键词： allergic asthma CD154 platelet regulatory T cells Th2 response

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Coexistence of Th1/Th2 and Thl7/Treg imbalances in patients with allergic asthma

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Chinese Medical Journal 2011年第13期124卷 1951-1956页

作者： SHI Yu-heng SHI Guo-chao WAN Huan-ying JIANG Li-hua AI Xiang-yan ZHU Hai-xing TANG Wei MA Jia-yun JIN Xiao-yan ZHANG Bo-ying Department of Pulmonary Medicine Ruijin HospitalShanghai Jiao Tong University School ofMedicine Shanghai 200025 China Shanghai Institute of Immunology Shanghai Jiao Tong University School ofMedicine Shanghai 206625 China 7 Department of Pulmonary Medicine Shanghai Third People'sHospital Shanghai 201900 China Department of Pulmonary Medicine Changning District CentreHospital Shanghai 200336 China Department of Pulmonary Medicine Luwan Branch of RuijinHospital Shanghai Jiao Tong University School of MedicineShanghai 200020 China

Background Recent recognition is that Th2 response is insufficient to fully explain the aetiology of asthma. Other CD4^＋ T cells subsets might play a role in asthma. We investigated the relative abundance and activities of Thl, Th2, Th17 and CD4^＋CD25^＋ Treg cells in patients with allergic asthma. Methods Twenty-two patients with mild asthma, 17 patients with moderate to severe asthma and 20 healthy donors were enrolled. All patients were allergic to house dust mites. Plasma total IgE, pulmonary function and asthma Control Questionnaire were assessed. The proportions of peripheral blood Thl, Th2, Th17 and CD4^＋CD25^＋ Treg cells were determined by flow cytometry. The expression of cytokines in plasma and Jn the culture supernatant of peripheral blood mononuclear cells was determined by enzyme linked, immunosorbent assay. Results The frequency of blood Th2 cells and IL-4 levels in plasma and culture supernatant of peripheral blood mononuclear cells were increased in all patients with allergic asthma. The frequency of Th17 cells and the plasma and culture supernatant levels of IL-17 were increased, whereas the frequency of CD4^＋CD25^＋ Treg cells and plasma IL-10 levels were decreased in patients with moderate to severe asthma. Dermatophagoides pteronyssinus specific IgE levels were positively correlated with the percentage of blood Th2 cells and plasma IL-4 levels. Forced expiratory volume in the first second was negatively correlated with the frequency of Th17 cells and plasma IL-17 levels, and positively correlated with the frequency of Treg cells. However, mean asthma Control Questionnaire scores were positively correlated with the frequency of Th17 cells and plasma IL-17 levels, and negatively correlated with the frequency of Treg cells. Conclusions Imbalances in Thl/Th2 and Th17/Treg were found in patients with allergic asthma. Furthermore, elevated Th17 cell responses, the absence of Tregs and an imbalance in Th17/Treg levels were associated with moderate to severe asthma.

关键词： allergic asthma Thl cells Th2 cells Thl 7 cells regulatory T cells

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Possible association of a distinct combined Glutathione-S-transferase members with allergic asthma patients in Pakistan

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Genes & Diseases 2017年第2期4卷 111-115页

作者： Aamna Dar Rani Faryal Nosheen Masood Department of Microbiology Quaid e Azam UniversityIslamabadPakistan Department of Environmental Sciences/Biotechnology Fatima Jinnah Women UniversityRawalpindiPakistan

allergic asthma is a diverse chronic respiratory disease characterized by the inflammation of the lower airway disease affecting many people around the world with rising morbidity and mortality.Association between asthma and certain demographic features was studied in relation to genotype from 244 allergic individuals of local population.Skin prick test was used to confirm asthma.Genetic polymorphism in Glutathione-S-transferases(GSTs)was studied using multiplex PCR based method and IgE level by ELISA.Pollen and dust were the major causative aeroallergens(26%),which were associated to higher IgE levels(Pasthma in only males(P Z 0.004).A low prevalence of null genotype of both GSTM1 and GSTT1 genes was observed in the patients(4.34%)compared to control group(14%).No association of combined GSTM1 and GSTT1 null genotype was found with the asthma in local population.GSTM1t and GSTTgenotype had higher risk(OR Z 1.3681,P Z 0.001)for development of asthma.There was a significant association of asthma with combined genotype of GSTM1t and GSTTwhen data was analyzed on gender basis in males(P Z 0.006)and highly significant in age range of 26e40 years(P Z 0.001).Combined GSTMt and GSTTgenotype was found to be risk factor for asthma in addition to family history in male patients.However a data with large patient size and different ethnic distribution may reveal the exact etiology.

关键词： allergic asthma Genetic polymorphism GSTM GSTT GST deletions Mutations

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Immune Homeostasis: Effects of Chinese Herbal Formulae and Herb-Derived Compounds on allergic asthma in Different Experimental Models

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Chinese Journal of Integrative Medicine 2018年第5期24卷 390-398页

作者： LIU Lu WANG Lin-peng HE Shan MA Yan Acupuncture and Moxibustion Department Beijing Hospital of Traditional Chinese Medicine Capital Medical University University Course of Traditional Chinese Medicine Medical University of Vienna Molecular Research in Traditional Chinese Medicine Group Department of Pathophysiology and Allergy Research Vienna General Hospital Medical University of Vienna

allergic asthma is thought to arise from an imbalance of immune regulation, which is characterized by the production of large quantities of Ig E antibodies by B cells and a decrease of the interferon-γ/interleukin-4(Th1/Th2) ratio. Certain immunomodulatory components and Chinese herbal formulae have been used in traditional herbal medicine for thousands of years. However, there are few studies performing evidence-based Chinese medicine(CM) research on the mechanisms and efficacy of these drugs in allergic asthma. This review aims to explore the roles of Chinese herbal formulae and herb-derived compounds in experimental research models of allergic asthma. We screened published modern CM research results on the experimental effects of Chinese herbal formulae and herb-derived bioactive compounds for allergic asthma and their possible underlying mechanisms in English language articles from the Pub Med and the Google Scholar databases with the keywords allergic asthma, experimental model and Chinese herbal medicine. We found 22 Chinese herb species and 31 herb-derived anti-asthmatic compounds as well as 12 Chinese herbal formulae which showed a reduction of airway hyperresponsiveness, allergen-specific immunoglobulin E, inflammatory cell infiltration and a regulation of Th1 and Th2 cytokines in vivo, in vitro and ex vivo, respectively. Chinese herbal formulae and herbderived bioactive compounds exhibit immunomodulatory, anti-inflammatory and anti-asthma activities in different experimental models and their various mechanisms of action are being investigated in modern CM research with genomics, proteomics and metabolomics technologies, which will lead to a new era in the development of new drug discovery for allergic asthma in CM.

关键词： immune homeostasis Chinese herbal medicine allergic asthma experimental model database

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Allergen specifi c sublingual immunotherapy in children with asthma and allergic rhinitis

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世界儿科杂志:英文版 2016年第3期12卷 283-290页

作者： Ivana Duric-Filipovic Marco Caminati Gordana Kostic Dorde Filipovic Zorica Zivkovic Faculty of Medical Science Kragujevac Department of ImmunologySvetozara Markovica 6934000 KragujevacSerbia Unita di Allergologia Centro Regionale di riferimento per la prevenzione la diagnosi e la terapia delle malattie allergiche Ospedale Universitario Borgo TrentoPiazzale Stefani 1VeronaItaly Children's Hospital Clinical Centre KragujevacZmaj Jovina 3034000 KragujevacSerbia Institution for Emergency Medical Care Bulevar Fransa Depera 511000 BelgradeSerbia Children's Hospital for Lung Diseases and Tuberculosis Medical Center"Dr Dragisa Misovic"Heroja Mihajla Tepica 111000 BelgradeSerbia

Background:The incidence of asthma and allergic rhinitis(AR)is significantly increased,especially in younger children.Current treatment for children with asthma and allergic rhinitis include allergen avoidance,standard pharmacotherapy,and immunotherapy.Since standard pharmacotherapy is prescribed for symptoms,immunotherapy at present plays an important role in the treatment of allergic diseases.This article presents insights into the up-to-date understanding of immunotherapy in the treatment of children with allergic rhinitis and asthma.Data sources:PubMed articles published from 1990 to 2014 were reviewed using the MeSH terms"asthma","allergic rhinitis","children",and"immune therapy".Additional articles were identified by hand searching of the references in the initial search.Results:Numerous studies have shown that sublingual application of allergen specifi c immunotherapy(SLIT)is an adequate,safe and effi cient substitution to subcutaneous route of allergens administration(SCIT)in the treatment of IgE-mediated respiratory tract allergies in children.According to the literature,better clinical efficacy is connected with the duration of treatment and mono sensitized patients.Conclusions:At least 3 years of treatment and stable asthma before the immunotherapy are positive predictors of good clinical efficacy and tolerability of SLIT.SLIT reduces the symptoms of allergic diseases and the use of medicaments,and improves the quality of life of children with the diseases.

关键词： allergic asthma allergic rhinitis allergic sensitization immunotherapy

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High-throughput 16S rDNA sequencing of the pulmonary microbiome of rats with allergic asthma

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Genes & Diseases 2020年第2期7卷 272-282页

作者： Yang Xiong Sen Hu Hongyao Zhou Hui Zeng Xuan He Dongni Huang Xiaoyu Li Department of the First Clinical Medicine Chongqing Medical UniversityChongqing400016China College of Stomatology Chongqing Medical UniversityChongqing401331China Department of the Second Clinical Medicine Chongqing Medical UniversityChongqing400016China Department of Obstetrics First Affiliated HospitalChongqing Medical UniversityChongqing400016China Laboratory of Innovation Basic Medical Experimental Teaching CenterChongqing Medical UniversityChongqing401331China

A decrease in microbial infection in adolescents is implicated with an increase in the incidence of asthma and allergic diseases in adulthood,indicating that the microbiome plays a critical role in asthma.However,the microbial composition of the lower respiratory tract remains unclear,hindering the further exploration of the pathogenesis of asthma.This study aims to explore the microbial distribution and composition in the lungs of normal rats and rats with allergic asthma via 16S rDNA sequencing.The DNA of the pulmonary microbiome was extracted from the left lungs collected from normal control group(NC),saline control group(SC),and allergic asthma group(AA)under aseptic conditions.After the 16s rDNA V4eV5 region was amplified,the products were sequenced using Illumina high-throughput technology and subjected to operational taxonomic unit(OTU)cluster and taxonomy analysis.The OTU values of AA increased significantly compared with those of NC and SC.Microbiome structure analysis showed that the dominant phylum of the pulmonary microbiome changed from Proteobacteria in NC to Firmicutes in AA.Linear discriminant analysis indicated that the key microbiomes involved in the three groups varied.

关键词： 16S rDNA allergic asthma Illumina sequencing Pulmonary microbiome Rats

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