Johanna Krusche1, Monika Twardziok2, Katharina Rehbach2, Andreas Böck2, Miranda S Tsang3, Paul C Schröder2, Jörg Kumbrink4, Thomas Kirchner4, Yuhan Xing5, Josef Riedler6, Jean-Charles Dalphin7, Juha Pekkanen8, Roger Lauener9, Marjut Roponen10, Jing Li11, Chun K Wong12, Gary W K Wong13, Bianca Schaub14. 1. Pediatric Allergology, Department of Pediatrics, Dr von Hauner Children's Hospital, University Hospital, LMU Munich, Munich, Germany; Member of the German Center for Lung Research-DZL, LMU Munich, Munich, Germany. 2. Pediatric Allergology, Department of Pediatrics, Dr von Hauner Children's Hospital, University Hospital, LMU Munich, Munich, Germany. 3. Institute of Chinese Medicine, Chinese University of Hong Kong, Hong Kong, China. 4. Institute of Pathology, Medical Faculty, LMU Munich, Munich, Germany; German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany. 5. Department of Paediatrics, Faculty of Medicine, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong, China. 6. Children's Hospital Schwarzach, Schwarzach, Austria, Teaching Hospital of Paracelsus Medical Private University Salzburg, Salzburg, Austria. 7. University Hospital of Besançon, UMR CNRS 6249 Chrono-Environment, University of Franche-Comté, Besançon, France. 8. Department of Health Security, National Institute for Health and Welfare (THL), Kuopio, Finland; Department of Public Health, University of Helsinki, Helsinki, Finland. 9. Children's Hospital of Eastern Switzerland, St Gallen, Switzerland; University of Zurich, Zurich, Switzerland; School of Medicine, University of St Gallen, St Gallen, Switzerland; Christine Kühne-Center for Allergy Care and Education, CK-CARE, Davos, Switzerland. 10. Department of Environmental and Biological Sciences, University of Eastern Finland, Kuopio, Finland. 11. Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Department of Allergy and Clinical Immunology, Guangzhou, China. 12. Department of Chemical Pathology, Chinese University of Hong Kong, Shatin, NT, Hong Kong, China. 13. Department of Paediatrics, Faculty of Medicine, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong, China. Electronic address: wingkinwong@cuhk.edu.hk. 14. Pediatric Allergology, Department of Pediatrics, Dr von Hauner Children's Hospital, University Hospital, LMU Munich, Munich, Germany; Member of the German Center for Lung Research-DZL, LMU Munich, Munich, Germany. Electronic address: Bianca.Schaub@med.uni-muenchen.de.
Abstract
BACKGROUND: Childhood asthma prevalence is significantly greater in urban areas compared with rural/farm environments. Murine studies have shown that TNF-α-induced protein 3 (TNFAIP3; A20), an anti-inflammatory regulator of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, mediates environmentally induced asthma protection. OBJECTIVE: We aimed to determine the role of TNFAIP3 for asthma development in childhood and the immunomodulatory effects of environmental factors. METHODS: In a representative selection of 250 of 2168 children from 2 prospective birth cohorts and 2 cross-sectional studies, we analyzed blood cells of healthy and asthmatic children from urban and rural/farm environments from Europe and China. PBMCs were stimulated ex vivo with dust from "asthma-protective" farms or LPS. NF-κB signaling-related gene and protein expression was assessed in PBMCs and multiplex gene expression assays (NanoString Technologies) in isolated dendritic cells of schoolchildren and in cord blood mononuclear cells from newborns. RESULTS: Anti-inflammatory TNFAIP3 gene and protein expression was consistently decreased, whereas proinflammatory Toll-like receptor 4 expression was increased in urban asthmatic patients (P < .05), reflecting their increased inflammatory status. Ex vivo farm dust or LPS stimulation restored TNFAIP3 expression to healthy levels in asthmatic patients and shifted NF-κB signaling-associated gene expression toward an anti-inflammatory state (P < .001). Farm/rural children had lower expression, indicating tolerance induction by continuous environmental exposure. Newborns with asthma at school age had reduced TNFAIP3 expression at birth, suggesting TNFAIP3 as a possible biomarker predicting subsequent asthma. CONCLUSION: Our data indicate TNFAIP3 as a key regulator during childhood asthma development and its environmentally mediated protection. Because environmental dust exposure conferred the anti-inflammatory effects, it might represent a promising future agent for asthma prevention and treatment.
BACKGROUND: Childhood asthma prevalence is significantly greater in urban areas compared with rural/farm environments. Murine studies have shown that TNF-α-induced protein 3 (TNFAIP3; A20), an anti-inflammatory regulator of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, mediates environmentally induced asthma protection. OBJECTIVE: We aimed to determine the role of TNFAIP3 for asthma development in childhood and the immunomodulatory effects of environmental factors. METHODS: In a representative selection of 250 of 2168 children from 2 prospective birth cohorts and 2 cross-sectional studies, we analyzed blood cells of healthy and asthmatic children from urban and rural/farm environments from Europe and China. PBMCs were stimulated ex vivo with dust from "asthma-protective" farms or LPS. NF-κB signaling-related gene and protein expression was assessed in PBMCs and multiplex gene expression assays (NanoString Technologies) in isolated dendritic cells of schoolchildren and in cord blood mononuclear cells from newborns. RESULTS: Anti-inflammatory TNFAIP3 gene and protein expression was consistently decreased, whereas proinflammatory Toll-like receptor 4 expression was increased in urban asthmatic patients (P < .05), reflecting their increased inflammatory status. Ex vivo farm dust or LPS stimulation restored TNFAIP3 expression to healthy levels in asthmatic patients and shifted NF-κB signaling-associated gene expression toward an anti-inflammatory state (P < .001). Farm/rural children had lower expression, indicating tolerance induction by continuous environmental exposure. Newborns with asthma at school age had reduced TNFAIP3 expression at birth, suggesting TNFAIP3 as a possible biomarker predicting subsequent asthma. CONCLUSION: Our data indicate TNFAIP3 as a key regulator during childhood asthma development and its environmentally mediated protection. Because environmental dust exposure conferred the anti-inflammatory effects, it might represent a promising future agent for asthma prevention and treatment.
Authors: Heleen Vroman; Denise van Uden; Ingrid M Bergen; Jennifer A C van Hulst; Melanie Lukkes; Geert van Loo; Björn E Clausen; Louis Boon; Bart N Lambrecht; Hamida Hammad; Rudi W Hendriks; Mirjam Kool Journal: Allergy Date: 2020-06-14 Impact factor: 13.146