Alexandra Schröder1,2, Lars P Lunding1,2, Ulrich M Zissler3,4, Christina Vock2,5, Sina Webering1,2, Johanna C Ehlers2,5, Zane Orinska2,5, Adam Chaker3,6, Carsten B Schmidt-Weber3,4, Niklas J Lang4,7, Herbert B Schiller4,7, Marcus A Mall8,9,10, Heinz Fehrenbach2,5, Charles A Dinarello11,12, Michael Wegmann1,2. 1. Division of Asthma Exacerbation &-Regulation, Priority Area Asthma & Allergy, Research Center Borstel-Leibniz Lung Center, Borstel, Germany. 2. Airway Research Center North, Member of the German Center for Lung Research (DZL), Munich, Germany. 3. Center of Allergy and Environment (ZAUM), Technische Universität and Helmholtz Center Munich, Member of the German Center for Lung Research (DZL), Munich, Germany. 4. Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research (DZL), Munich, Germany. 5. Division of Experimental Pneumology, Priority Area Asthma & Allergy, Research Center Borstel- Leibniz Lung Center, Borstel, Germany. 6. Department of Otorhinolaryngology and Head and Neck Surgery, Medical School, Technical, University of Munich, Munich, Germany. 7. Institute of Lung Biology and Disease, Helmholtz Zentrum München, Munich, Germany. 8. Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Charité - Universitätsmedizin Berlin, Berlin, Germany. 9. Berlin Institute of Health (BIH), Berlin, Germany. 10. German Center for Lung Research (DZL), associated partner site, Berlin, Germany. 11. Department of Medicine, University of Colorado Denver, Denver, CO, USA. 12. Department of Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
Abstract
BACKGROUND: Children with asthma have impaired production of interleukin (IL) 37; in mice, IL-37 reduces hallmarks of experimental allergic asthma (EAA). However, it remains unclear how IL-37 exerts its inhibitory properties in asthma. This study aimed to identify the mechanism(s) by which IL-37 controls allergic inflammation. METHODS: IL-37 target cells were identified by single-cell RNA-seq of IL-1R5 and IL-1R8. Airway tissues were isolated by laser-capture microdissection and examined by microarray-based gene expression analysis. Mononuclear cells (MNC) and airway epithelial cells (AECs) were isolated and stimulated with allergen, IL-1β, or IL-33 together with recombinant human (rh) IL-37. Wild-type, IL-1R1- and IL-33-deficient mice with EAA were treated with rhIL-37. IL-1β, IL-33, and IL-37 levels were determined in sputum and nasal secretions from adult asthma patients without glucocorticoid therapy. RESULTS: IL-37 target cells included AECs, T cells, and dendritic cells. In mice with EAA, rhIL-37 led to differential expression of >90 genes induced by IL-1β and IL-33. rhIL-37 reduced production of Th2 cytokines in allergen-activated MNCs from wild-type but not from IL-1R1-deficient mice and inhibited IL-33-induced Th2 cytokine release. Furthermore, rhIL-37 attenuated IL-1β- and IL-33-induced pro-inflammatory mediator expression in murine AEC cultures. In contrast to wild-type mice, hIL-37 had no effect on EAA in IL-1R1- or IL-33-deficient mice. We also observed that expression/production ratios of both IL-1β and IL-33 to IL-37 were dramatically increased in asthma patients compared to healthy controls. CONCLUSION: IL-37 downregulates allergic airway inflammation by counterbalancing the disease-amplifying effects of IL-1β and IL-33.
BACKGROUND: Children with asthma have impaired production of interleukin (IL) 37; in mice, IL-37 reduces hallmarks of experimental allergic asthma (EAA). However, it remains unclear how IL-37 exerts its inhibitory properties in asthma. This study aimed to identify the mechanism(s) by which IL-37 controls allergic inflammation. METHODS: IL-37 target cells were identified by single-cell RNA-seq of IL-1R5 and IL-1R8. Airway tissues were isolated by laser-capture microdissection and examined by microarray-based gene expression analysis. Mononuclear cells (MNC) and airway epithelial cells (AECs) were isolated and stimulated with allergen, IL-1β, or IL-33 together with recombinant human (rh) IL-37. Wild-type, IL-1R1- and IL-33-deficient mice with EAA were treated with rhIL-37. IL-1β, IL-33, and IL-37 levels were determined in sputum and nasal secretions from adult asthma patients without glucocorticoid therapy. RESULTS: IL-37 target cells included AECs, T cells, and dendritic cells. In mice with EAA, rhIL-37 led to differential expression of >90 genes induced by IL-1β and IL-33. rhIL-37 reduced production of Th2 cytokines in allergen-activated MNCs from wild-type but not from IL-1R1-deficient mice and inhibited IL-33-induced Th2 cytokine release. Furthermore, rhIL-37 attenuated IL-1β- and IL-33-induced pro-inflammatory mediator expression in murine AEC cultures. In contrast to wild-type mice, hIL-37 had no effect on EAA in IL-1R1- or IL-33-deficient mice. We also observed that expression/production ratios of both IL-1β and IL-33 to IL-37 were dramatically increased in asthma patients compared to healthy controls. CONCLUSION: IL-37 downregulates allergic airway inflammation by counterbalancing the disease-amplifying effects of IL-1β and IL-33.
Authors: Agata Wypych-Ślusarska; Martina Grot; Maria Kujawińska; Maciej Nigowski; Karolina Krupa-Kotara; Klaudia Oleksiuk; Joanna Głogowska-Ligus; Mateusz Grajek Journal: Int J Environ Res Public Health Date: 2022-09-06 Impact factor: 4.614