Plasmacytoid dendritic cells drive acute asthma exacerbations - 30/11/17
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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.
Le texte complet de cet article est disponible en PDF.Graphical abstract |
Key words : Plasmacytoid dendritic cells, asthma, animal models of allergic airway disease, rhinovirus, asthma exacerbations
Abbreviations used : AAD, BAL, BDCA-2, CRLF2, FITC, ILC2, MLN, ODN, OVA, OX40L, pDC, PDCA-1, Siglec-H, TLR, TSLP
Plan
| Supported by core funding from the Hellenic Ministries of Health and Education and by grant awards from the Hellenic Ministry of Education (“Thalis” Programme MIDAS and “Excellence” Programme RESOLVE-ASTHMA) and the European Commission (FP7 Programmes PREDICTA, NILTHERA and TACIT). |
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| Disclosure of potential conflict of interest: A.-D. Chairakaki has received grants from the European Commission and the Greek government (Ministry of Education and Religious Affairs). R. P. Walton is a board member/director for and has consultant arrangements with Therapeutic Frontiers. N. W. Bartlett has consultant arrangements with Abeome, is employed by Imperial College London and the University of Newcastle, has received grants from the Medical Research Council and Abeome, is an inventor on US nonprovisional patent 30817 owned by Abeome, has received stock options from Abeome, and has received travel support from Abeome. N. Rovina has participated in advisory boards for Novartis, AstraZeneca, Chiesi, and Menarini and has received payment for lectures from Chiesi, Novartis, Elpen, and Boehringer. N. G. Papadopoulos has board memberships with Novartis, Faes Farma, Biomay, HAL, and Nutricia Research; has consultant arrangements with Menarinin, Novartis, and MEDA; has received grants from Menarini; and has received payment for lectrues from Abbvie, Novartis, MEDA, MSD, MEDA, Omega Pharma, and Danone. S. L. Johnston has received grants from Centocor, GlaxoSmithKline, Chiesi, Boehringer Ingelheim, Novartis, and Synairgen; has received personal fees from Centocor, Sanofi Pasteur, GlaxoSmithKline, Chiesi, Boehringer Ingelheim, Novartis, Synairgen, Aviragen, Bayer, Concert Pharmaceuticals, and Myelo Therapeutics; is co-owner of a patent with Sanofi Pasteur; is a shareholder in Synairgen; is director and a shareholder in Therapeutic Frontiers; has a patent (Blair ED, Killington RA, Rowlands DJ, Clarke NJ, Johnston SL. Transgenic animal models of HRV with human ICAM-1 sequences. UK patent application no. 02 167 29.4 [July 18, 2002] and International patent application no. PCT/EP2003/007939 [July 17, 2003], licensed); has a patent (Wark PA, Johnston SL, Holgate ST, Davies DE. Anti-virus therapy for respiratory diseases. UK patent application no. GB 0405634.7 [March 12, 2004], licensed), has a patent (Wark PA, Johnston SL, Holgate ST, Davies DE. Interferon-Beta for anti-virus therapy for respiratory diseases. International patent application no. PCT/GB05/50031 [March 12, 2004], licensed); has a patent (Wark PA, Johnston SL, Holgate ST, Davies DE. The use of interferon lambda for the treatment and prevention of virally-induced exacerbation in asthma and chronic pulmonary obstructive disease. UK patent application no. 0518425.4 [September 9, 2005], licensed); has a patent (Wark PA, Johnston SL, Holgate ST, Davies DE. Anti-virus therapy for respiratory diseases. US patent application 11/517,763, patent no. 7569216, National Phase of PCT/GB2005/050031 [August 4, 2009], licensed); has a patent (Wark PA, Johnston SL, Holgate ST, Davies DE. Interferon-beta for anti-virus therapy for respiratory diseases. European patent no. 1734987 [May 5, 2010], licensed); has a patent (Wark PA, Johnston SL, Holgate ST, Davies DE. Anti-virus therapy for respiratory diseases [IFNb therapy]. Hong Kong patent no. 1097181 [August 31, 2010], licensed); has a patent (Wark PA, Johnston SL, Holgate ST, Davies DE. Anti-virus therapy for respiratory diseases [IFNb therapy]. Japanese patent no. 4807526 [August 26, 2011], licensed); has a patent (Wark PA, Johnston SL, Holgate ST, Davies DE. Interferon-beta for anti-virus therapy for respiratory diseases. New Hong Kong–divisional patent application no. 11100187.0 [January 10, 2011], licensed); and has a patent (Burdin N, Almond J, Lecouturieir, V, Girerd-Chambaz Y, Guy, B, Bartlett N, Walton R, McLean G, Glanville N, Johnston SL. Induction of cross-reactive cellular response against rhinovirus antigens. European patent no. 13305152 [April 4, 2013], pending). E. Andreakos has received grants from the European Commission and the Greek Ministry of Education and Religious Affairs. The rest of the authors declare that they have no relevant conflicts of interest. |
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