Denise Rauer1, Stefanie Gilles1, Maria Wimmer2,3, Ulrike Frank4, Constanze Mueller5, Stephanie Musiol2,3, Behnam Vafadari1, Lorenz Aglas6, Fatima Ferreira6, Philippe Schmitt-Kopplin5, Jörg Durner4, Jana Barbro Winkler7, Dieter Ernst4, Heidrun Behrendt2, Carsten B Schmidt-Weber2,3, Claudia Traidl-Hoffmann1,8,9, Francesca Alessandrini2,3. 1. Chair and Institute of Environmental Medicine, UNIKA-T, Technical University of Munich and Helmholtz Zentrum München, Augsburg, Germany. 2. Center of Allergy & Environment (ZAUM), Technical University of Munich (TUM) and Helmholtz Zentrum München, Munich, Germany. 3. Members of the German Center of Lung Research (DZL), Munich, Germany. 4. Institute of Biochemical Plant Pathology (BIOP), Helmholtz Zentrum München, Neuherberg, Germany. 5. BGC, Research Unit Analytical BioGeoChemistry, Helmholtz Zentrum München, Neuherberg, Germany. 6. Department of Biosciences, University of Salzburg, Salzburg, Austria. 7. Research Unit Environmental Simulation, Institute of Biochemical Plant Pathology, Helmholtz Zentrum München, Neuherberg, Germany. 8. Outpatient Clinic for Environmental Medicine, University Clinic Augsburg, Augsburg, Germany. 9. Christine-Kühne Center for Allergy Research and Education (CK-Care), Davos, Switzerland.
Abstract
BACKGROUND: Common ragweed has been spreading as a neophyte in Europe. Elevated CO2 levels, a hallmark of global climate change, have been shown to increase ragweed pollen production, but their effects on pollen allergenicity remain to be elucidated. METHODS: Ragweed was grown in climate-controlled chambers under normal (380 ppm, control) or elevated (700 ppm, based on RCP4.5 scenario) CO2 levels. Aqueous pollen extracts (RWE) from control- or CO2 -pollen were administered in vivo in a mouse model for allergic disease (daily for 3-11 days, n = 5) and employed in human in vitro systems of nasal epithelial cells (HNECs), monocyte-derived dendritic cells (DCs), and HNEC-DC co-cultures. Additionally, adjuvant factors and metabolites in control- and CO2 -RWE were investigated using ELISA and untargeted metabolomics. RESULTS: In vivo, CO2 -RWE induced stronger allergic lung inflammation compared to control-RWE, as indicated by lung inflammatory cell infiltrate and mediators, mucus hypersecretion, and serum total IgE. In vitro, HNECs stimulated with RWE increased indistinctively the production of pro-inflammatory cytokines (IL-8, IL-1β, and IL-6). In contrast, supernatants from CO2 -RWE-stimulated HNECs, compared to control-RWE-stimulated HNECS, significantly increased TNF and decreased IL-10 production in DCs. Comparable results were obtained by stimulating DCs directly with RWEs. The metabolome analysis revealed differential expression of secondary plant metabolites in control- vs CO2 -RWE. Mixes of these metabolites elicited similar responses in DCs as compared to respective RWEs. CONCLUSION: Our results indicate that elevated ambient CO2 levels elicit a stronger RWE-induced allergic response in vivo and in vitro and that RWE increased allergenicity depends on the interplay of multiple metabolites.
BACKGROUND:Common ragweed has been spreading as a neophyte in Europe. Elevated CO2 levels, a hallmark of global climate change, have been shown to increase ragweed pollen production, but their effects on pollen allergenicity remain to be elucidated. METHODS:Ragweed was grown in climate-controlled chambers under normal (380 ppm, control) or elevated (700 ppm, based on RCP4.5 scenario) CO2 levels. Aqueous pollen extracts (RWE) from control- or CO2 -pollen were administered in vivo in a mouse model for allergic disease (daily for 3-11 days, n = 5) and employed in human in vitro systems of nasal epithelial cells (HNECs), monocyte-derived dendritic cells (DCs), and HNEC-DC co-cultures. Additionally, adjuvant factors and metabolites in control- and CO2 -RWE were investigated using ELISA and untargeted metabolomics. RESULTS: In vivo, CO2 -RWE induced stronger allergic lung inflammation compared to control-RWE, as indicated by lung inflammatory cell infiltrate and mediators, mucus hypersecretion, and serum total IgE. In vitro, HNECs stimulated with RWE increased indistinctively the production of pro-inflammatory cytokines (IL-8, IL-1β, and IL-6). In contrast, supernatants from CO2 -RWE-stimulated HNECs, compared to control-RWE-stimulated HNECS, significantly increased TNF and decreased IL-10 production in DCs. Comparable results were obtained by stimulating DCs directly with RWEs. The metabolome analysis revealed differential expression of secondary plant metabolites in control- vs CO2 -RWE. Mixes of these metabolites elicited similar responses in DCs as compared to respective RWEs. CONCLUSION: Our results indicate that elevated ambient CO2 levels elicit a stronger RWE-induced allergic response in vivo and in vitro and that RWE increased allergenicity depends on the interplay of multiple metabolites.