Aikaterini-Dimitra Chairakaki1, Maria-Ioanna Saridaki1, Katerina Pyrillou1, Marios-Angelos Mouratis1, Ourania Koltsida2, Ross P Walton3, Nathan W Bartlett4, Athanasios Stavropoulos1, Louis Boon5, Nikoletta Rovina6, Nikolaos G Papadopoulos7, Sebastian L Johnston3, Evangelos Andreakos8. 1. Department of Immunology, Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece. 2. Department of Immunology, Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece; 1(st) Department of Respiratory Medicine, Medical School, National Kapodistrian University of Athens, "Sotiria" Regional Chest Diseases Hospital, Athens, Greece. 3. Airway Disease Infection Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom. 4. Airway Disease Infection Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom; Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and University of Newcastle, Newcastle, Australia. 5. Bioceros, Utrecht, The Netherlands. 6. 1(st) Department of Respiratory Medicine, Medical School, National Kapodistrian University of Athens, "Sotiria" Regional Chest Diseases Hospital, Athens, Greece. 7. Institute of Human Development, University of Manchester, Manchester, United Kingdom; A. Kyriakou Children's Hospital, National Kapodistrian University of Athens, Athens, Greece. 8. Department of Immunology, Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece. Electronic address: vandreakos@bioacademy.gr.
Abstract
BACKGROUND: Although acute exacerbations, mostly triggered by viruses, account for the majority of hospitalizations in asthmatic patients, there is still very little known about the pathophysiologic mechanisms involved. Plasmacytoid dendritic cells (pDCs), prominent cells of antiviral immunity, exhibit proinflammatory or tolerogenic functions depending on the context, yet their involvement in asthma exacerbations remains unexplored. OBJECTIVES: We sought to investigate the role of pDCs in allergic airway inflammation and acute asthma exacerbations. METHODS: Animal models of allergic airway disease (AAD) and virus-induced AAD exacerbations were used to dissect pDC function in vivo and unwind the potential mechanisms involved. Sputum from asthmatic patients with stable disease or acute exacerbations was further studied to determine the presence of pDCs and correlation with inflammation. RESULTS: pDCs were key mediators of the immunoinflammatory cascade that drives asthma exacerbations. In animal models of AAD and rhinovirus-induced AAD exacerbations, pDCs were recruited to the lung during inflammation and migrated to the draining lymph nodes to boost TH2-mediated effector responses. Accordingly, pDC depletion after allergen challenge or during rhinovirus infection abrogated exacerbation of inflammation and disease. Central to this process was IL-25, which was induced by allergen challenge or rhinovirus infection and conditioned pDCs for proinflammatory function. Consistently, in asthmatic patients pDC numbers were markedly increased during exacerbations and correlated with the severity of inflammation and the risk for asthma attacks. CONCLUSIONS: Our studies uncover a previously unsuspected role of pDCs in asthma exacerbations with potential diagnostic and prognostic implications. They also propose the therapeutic targeting of pDCs and IL-25 for the treatment of acute asthma.
BACKGROUND: Although acute exacerbations, mostly triggered by viruses, account for the majority of hospitalizations in asthmatic patients, there is still very little known about the pathophysiologic mechanisms involved. Plasmacytoid dendritic cells (pDCs), prominent cells of antiviral immunity, exhibit proinflammatory or tolerogenic functions depending on the context, yet their involvement in asthma exacerbations remains unexplored. OBJECTIVES: We sought to investigate the role of pDCs in allergic airway inflammation and acute asthma exacerbations. METHODS: Animal models of allergic airway disease (AAD) and virus-induced AAD exacerbations were used to dissect pDC function in vivo and unwind the potential mechanisms involved. Sputum from asthmatic patients with stable disease or acute exacerbations was further studied to determine the presence of pDCs and correlation with inflammation. RESULTS: pDCs were key mediators of the immunoinflammatory cascade that drives asthma exacerbations. In animal models of AAD and rhinovirus-induced AAD exacerbations, pDCs were recruited to the lung during inflammation and migrated to the draining lymph nodes to boost TH2-mediated effector responses. Accordingly, pDC depletion after allergen challenge or during rhinovirus infection abrogated exacerbation of inflammation and disease. Central to this process was IL-25, which was induced by allergen challenge or rhinovirus infection and conditioned pDCs for proinflammatory function. Consistently, in asthmatic patients pDC numbers were markedly increased during exacerbations and correlated with the severity of inflammation and the risk for asthma attacks. CONCLUSIONS: Our studies uncover a previously unsuspected role of pDCs in asthma exacerbations with potential diagnostic and prognostic implications. They also propose the therapeutic targeting of pDCs and IL-25 for the treatment of acute asthma.
Authors: Lauren M Webb; Alexander T Phythian-Adams; Alice H Costain; Sheila L Brown; Rachel J Lundie; Josephine Forde-Thomas; Peter C Cook; Lucy H Jackson-Jones; Angela K Marley; Hermelijn H Smits; Karl F Hoffmann; Elia D Tait Wojno; Andrew S MacDonald Journal: Immunohorizons Date: 2021-08-30
Authors: Xin Sun; Anne-Karina Perl; Rongbo Li; Sheila M Bell; Eniko Sajti; Vladimir V Kalinichenko; Tanya V Kalin; Ravi S Misra; Hitesh Deshmukh; Geremy Clair; Jennifer Kyle; Laura E Crotty Alexander; Jorge A Masso-Silva; Joseph A Kitzmiller; Kathryn A Wikenheiser-Brokamp; Gail Deutsch; Minzhe Guo; Yina Du; Michael P Morley; Michael J Valdez; Haoze V Yu; Kang Jin; Eric E Bardes; Jarod A Zepp; Terren Neithamer; Maria C Basil; William J Zacharias; Jamie Verheyden; Randee Young; Gautam Bandyopadhyay; Sara Lin; Charles Ansong; Joshua Adkins; Nathan Salomonis; Bruce J Aronow; Yan Xu; Gloria Pryhuber; Jeff Whitsett; Edward E Morrisey Journal: Dev Cell Date: 2021-12-21 Impact factor: 13.417