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      Directional Secretory Response of Double Stranded RNA-Induced Thymic Stromal Lymphopoetin (TSLP) and CCL11/Eotaxin-1 in Human Asthmatic Airways

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          Abstract

          Background

          Thymic stromal lymphoproetin (TSLP) is a cytokine secreted by the airway epithelium in response to respiratory viruses and it is known to promote allergic Th2 responses in asthma. This study investigated whether virally-induced secretion of TSLP is directional in nature (apical vs. basolateral) and/or if there are TSLP-mediated effects occurring at both sides of the bronchial epithelial barrier in the asthmatic state.

          Methods

          Primary human bronchial epithelial cells (HBEC) from control (n = 3) and asthmatic (n = 3) donors were differentiated into polarized respiratory tract epithelium under air-liquid interface (ALI) conditions and treated apically with dsRNA (viral surrogate) or TSLP. Sub-epithelial effects of TSLP were examined in human airway smooth muscle cells (HASMC) from normal (n = 3) and asthmatic (n = 3) donors. Clinical experiments examined nasal airway secretions obtained from asthmatic children during naturally occurring rhinovirus-induced exacerbations (n = 20) vs. non-asthmatic uninfected controls (n = 20). Protein levels of TSLP, CCL11/eotaxin-1, CCL17/TARC, CCL22/MDC, TNF-α and CXCL8 were determined with a multiplex magnetic bead assay.

          Results

          Our data demonstrate that: 1) Asthmatic HBEC exhibit an exaggerated apical, but not basal, secretion of TSLP after dsRNA exposure; 2) TSLP exposure induces unidirectional (apical) secretion of CCL11/eotaxin-1 in asthmatic HBEC and enhanced CCL11/eotaxin-1 secretion in asthmatic HASMC; 3) Rhinovirus-induced asthma exacerbations in children are associated with in vivo airway secretion of TSLP and CCL11/eotaxin-1.

          Conclusions

          There are virally-induced TSLP-driven secretory immune responses at both sides of the bronchial epithelial barrier characterized by enhanced CCL11/eotaxin-1 secretion in asthmatic airways. These results suggest a new model of TSLP-mediated eosinophilic responses in the asthmatic airway during viral-induced exacerbations.

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          Most cited references29

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          Respiratory viruses and exacerbations of asthma in adults.

          K Nicholson, J. Kent, D Ireland (1993)
          To study the role of respiratory viruses in exacerbations of asthma in adults. Longitudinal study of 138 adults with asthma. Leicestershire Health Authority. 48 men and 90 women 19-46 years of age with a mean duration of wheeze of 19.6 years. 75% received regular treatment with bronchodilators; 89% gave a history of eczema, hay fever, allergic rhinitis, nasal polyps, or allergies; 38% had been admitted to hospital with asthma. Symptomatic colds and asthma exacerbations; objective exacerbations of asthma with > or = 50 l/min reduction in mean peak expiratory flow rate when morning and night time readings on days 1-7 after onset of symptoms were compared with rates during an asymptomatic control period; laboratory confirmed respiratory tract infections. Colds were reported in 80% (223/280) of episodes with symptoms of wheeze, chest tightness, or breathlessness, and 89% (223/250) of colds were associated with asthma symptoms. 24% of 115 laboratory confirmed non-bacterial infections were associated with reductions in mean peak expiratory flow rate > or = 50 l/min through days 1-7 and 48% had mean decreases > or = 25 l/min. 44% of episodes with mean decreases in flow rate > or = 50 l/min were associated with laboratory confirmed infections. Infections with rhinoviruses, coronaviruses OC43 and 229E, influenza B, respiratory syncytial virus, parainfluenza virus, and chlamydia were all associated with objective evidence of an exacerbation of asthma. These findings show that asthma symptoms and reductions in peak flow are often associated with colds and respiratory viruses; respiratory virus infections commonly cause or are associated with exacerbations of asthma in adults.
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            Rhinovirus-induced modulation of gene expression in bronchial epithelial cells from subjects with asthma.

            Nizar Jarjour, S Keles, Yury Bochkov … (2009)
            Rhinovirus (RV) infections trigger asthma exacerbations. Genome-wide expression analysis of RV1A-infected primary bronchial epithelial cells from normal and asthmatic donors was performed to determine whether asthma is associated with a unique pattern of RV-induced gene expression. Virus replication rates were similar in cells from normal and asthmatic donors. Overall, RV downregulated 975 and upregulated 69 genes. Comparisons of transcriptional profiles generated from microarrays and confirmed by quantitative reverse transcription PCR and cluster analysis showed some up- and downregulated genes in asthma cells involved in immune responses (IL1B, IL1F9, IL24, and IFI44) and airway remodeling (LOXL2, MMP10, FN1). Notably, most of the asthma-related differences in RV-infected cells were also present in the cells before infection. These findings suggest that differences in RV-induced gene expression profiles of cells from normal and mild asthmatic subjects could affect the acute inflammatory response to RV, and subsequent airway repair and remodeling.
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              Thymic stromal lymphopoietin expression is increased in asthmatic airways and correlates with expression of Th2-attracting chemokines and disease severity.

              Guizhen Zhang, Sun Ying, David Cousins … (2005)
              Thymic stromal lymphopoietin (TSLP) is said to increase expression of chemokines attracting Th2 T cells. We hypothesized that asthma is characterized by elevated bronchial mucosal expression of TSLP and Th2-attracting, but not Th1-attracting, chemokines as compared with controls, with selective accumulation of cells bearing receptors for these chemokines. We used in situ hybridization and immunohistochemistry to examine the expression and cellular provenance of TSLP, Th2-attracting (thymus and activation-regulated chemokine (TARC)/CCL17, macrophage-derived chemokine (MDC)/CCL22, I-309/CCL1) and Th1-attracting (IFN-gamma-inducible protein 10 (IP-10)/CXCL10, IFN-inducible T cell alpha-chemoattractant (I-TAC)/CXCL11) chemokines and expression of their receptors CCR4, CCR8, and CXCR3 in bronchial biopsies from 20 asthmatics and 15 normal controls. The numbers of cells within the bronchial epithelium and submucosa expressing mRNA for TSLP, TARC/CCL17, MDC/CCL22, and IP-10/CXCL10, but not I-TAC/CXCL11 and I-309/CCL1, were significantly increased in asthmatics as compared with controls (p
              Article 0 comments Cited 123 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                John S. Tregoning: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2014
                Publication date (Electronic): 29 December 2014
                Volume: 9
                Issue: 12
                Electronic Location Identifier: e115398
                Affiliations
                [1 ]Division of Pulmonary and Sleep Medicine, Children's National Medical Center, Washington, DC, United States of America
                [2 ]Department of Pediatrics, George Washington University School of Medicine and Health Sciences, Washington, DC, United States of America
                [3 ]Department of Integrative Systems Biology, George Washington University, Washington, DC, United States of America
                [4 ]Center for Genetic Research Medicine, Children's National Medical Center, Washington, DC, United States of America
                [5 ]Department of Biochemistry and Molecular Medicine, George Washington University, Washington, DC, United States of America
                Imperial College London, United Kingdom
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: GN ACP DKP MCR. Performed the experiments: GN SH GP KP HM AA. Analyzed the data: GN JW SE. Wrote the paper: GN SH GP DKP ACP MCR.

                Article
                Publisher ID: PONE-D-14-33910
                DOI: 10.1371/journal.pone.0115398
                PMC ID: 4278901
                PubMed ID: 25546419
                SO-VID: 0e13542a-0235-49f9-9eb1-7a07ed2805d4
                Copyright statement: Copyright @ 2014
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 30 July 2014
                Date accepted : 21 November 2014
                Page count
                Pages: 19
                Funding
                This work was supported by Grants NHLBI/HL090020 (K12 Genomics of Lung), NICHC/HD001399 (K12 Child Health Research Career Development Award), UL1TR000075 KL2TR000076 Awards from the NIH National Center for Advancing Translational Sciences and a Board of Visitors (BOV) Grant of Children's National Medical Center. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Subject: Research Article
                Subject: Biology and Life Sciences
                Subject: Anatomy
                Subject: Biological Tissue
                Subject: Epithelium
                Subject: Epithelial Cells
                Subject: Respiratory System
                Subject: Lungs
                Subject: Cell Biology
                Subject: Cellular Types
                Subject: Animal Cells
                Subject: Immunology
                Subject: Clinical Immunology
                Subject: Immunotherapy
                Subject: Allergy Immunotherapy
                Subject: Medicine and Health Sciences
                Subject: Pediatrics
                Subject: Pediatric Pulmonology
                Subject: Pulmonology
                Subject: Asthma
                Subject: Research and Analysis Methods
                Subject: Biological Cultures
                Subject: Cell Culture Analysis
                Custom metadata
                Data Availability The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper.

                ScienceOpen disciplines: Uncategorized
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                ScienceOpen disciplines: Uncategorized

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