{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T03:36:03Z","timestamp":1790393763246,"version":"4.1.0"},"reference-count":41,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2020,5,17]],"date-time":"2020-05-17T00:00:00Z","timestamp":1589673600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"Conseil R\u00e9gional Nord Pas de Calais","award":["StreptoCOPD project"],"award-info":[{"award-number":["StreptoCOPD project"]}]},{"DOI":"10.13039\/501100001677","name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001677","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004794","name":"Centre National de la Recherche Scientifique","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004794","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,7,17]]},"abstract":"<jats:title>Summary<\/jats:title>\n               <jats:p>The progression of chronic obstructive pulmonary disease (COPD), a lung inflammatory disease being the fourth cause of death worldwide, is marked by acute exacerbations. These episodes are mainly caused by bacterial infections, frequently due to Streptococcus pneumoniae. This susceptibility to infection involves a defect in interleukin (IL)-22, which plays a pivotal role in mucosal defense mechanism. Administration of flagellin, a Toll-like receptor 5 (TLR-5) agonist, can protect mice and primates against respiratory infections in a non-pathological background. We hypothesized that TLR-5-mediated stimulation of innate immunity might improve the development of bacteria-induced exacerbations in a COPD context. Mice chronically exposed to cigarette smoke (CS), mimicking COPD symptoms, are infected with S. pneumoniae, and treated in a preventive and a delayed manner with flagellin. Both treatments induced a lower bacterial load in the lungs and blood, and strongly reduced the inflammation and lung lesions associated with the infection. This protection implicated an enhanced production of IL-22 and involved the recirculation of soluble factors secreted by spleen cells. This is also associated with higher levels of the S100A8 anti-microbial peptide in the lung. Furthermore, human mononuclear cells from non-smokers were able to respond to recombinant flagellin by increasing IL-22 production while active smoker cells do not, a defect associated with an altered IL-23 production. This study shows that stimulation of innate immunity by a TLR-5 ligand reduces CS-induced susceptibility to bacterial infection in mice, and should be considered in therapeutic strategies against COPD exacerbations.<\/jats:p>","DOI":"10.1111\/cei.13445","type":"journal-article","created":{"date-parts":[[2020,4,23]],"date-time":"2020-04-23T13:26:07Z","timestamp":1587648367000},"page":"171-186","source":"Crossref","is-referenced-by-count":12,"title":["Boosting the IL-22 response using flagellin prevents bacterial infection in cigarette smoke-exposed mice"],"prefix":"10.1093","volume":"201","author":[{"given":"B","family":"Kon\u00e9","sequence":"first","affiliation":[{"name":"Universit\u00e9 de Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"P\u00e9rez-Cruz","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R","family":"Porte","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F","family":"Hennegrave","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C","family":"Carnoy","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P","family":"Gosset","sequence":"additional","affiliation":[{"name":"Service d'Anatomo-pathologie, H\u00f4pital Saint Vincent de Paul, Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F","family":"Trottein","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J-C","family":"Sirard","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"Pichavant","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4043-6429","authenticated-orcid":false,"given":"P","family":"Gosset","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,5,17]]},"reference":[{"key":"2021121023213119200_cei13445-bib-0001","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1038\/nri2254","article-title":"Immunology of asthma and chronic obstructive pulmonary disease","volume":"8","author":"Barnes","year":"2008","journal-title":"Nat Rev Immunol"},{"key":"2021121023213119200_cei13445-bib-0002","doi-asserted-by":"crossref","first-page":"2095","DOI":"10.1016\/S0140-6736(12)61728-0","article-title":"Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010","volume":"380","author":"Lozano","year":"2012","journal-title":"Lancet"},{"key":"2021121023213119200_cei13445-bib-0003","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1016\/S0140-6736(04)16855-4","article-title":"Burden and clinical features of chronic obstructive pulmonary disease (COPD)","volume":"364","author":"Pauwels","year":"2004","journal-title":"Lancet"},{"key":"2021121023213119200_cei13445-bib-0004","doi-asserted-by":"crossref","first-page":"1015","DOI":"10.1016\/S0140-6736(11)60988-4","article-title":"New insights into the immunology of chronic obstructive pulmonary disease","volume":"378","author":"Brusselle","year":"2011","journal-title":"Lancet"},{"key":"2021121023213119200_cei13445-bib-0005","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1038\/mi.2013.75","article-title":"Oxidative stress-mediated iNKT-cell activation is involved in COPD pathogenesis","volume":"7","author":"Pichavant","year":"2014","journal-title":"Mucosal Immunol"},{"key":"2021121023213119200_cei13445-bib-0006","doi-asserted-by":"crossref","first-page":"1341","DOI":"10.1016\/S0140-6736(11)60968-9","article-title":"Chronic obstructive pulmonary disease","volume":"379","author":"Decramer","year":"2012","journal-title":"Lancet"},{"key":"2021121023213119200_cei13445-bib-0007","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1056\/NEJMoa012561","article-title":"New strains of bacteria and exacerbations of chronic obstructive pulmonary disease","volume":"347","author":"Sethi","year":"2002","journal-title":"N Engl J Med"},{"key":"2021121023213119200_cei13445-bib-0008","doi-asserted-by":"crossref","first-page":"2472","DOI":"10.1016\/j.rmed.2007.07.015","article-title":"A community-based, time-matched, case-control study of respiratory viruses and exacerbations of COPD","volume":"101","author":"Hutchinson","year":"2007","journal-title":"Respir Med"},{"key":"2021121023213119200_cei13445-bib-0009","doi-asserted-by":"crossref","first-page":"2581","DOI":"10.2147\/COPD.S88702","article-title":"Bacterial flora in the sputum and comorbidity in patients with acute exacerbations of COPD","volume":"10","author":"Boixeda","year":"2015","journal-title":"Int J Chron Obstruct Pulmon Dis"},{"key":"2021121023213119200_cei13445-bib-0010","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1111\/resp.12734","article-title":"COPD is characterized by increased detection of Haemophilus influenzae, Streptococcus pneumoniae and a deficiency of Bacillus species","volume":"21","author":"Simpson","year":"2016","journal-title":"Respirology"},{"key":"2021121023213119200_cei13445-bib-0011","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1111\/j.1462-5822.2011.01746.x","article-title":"Recognition of Streptococcus pneumoniae by the innate immune system","volume":"14","author":"Koppe","year":"2012","journal-title":"Cell Microbiol"},{"key":"2021121023213119200_cei13445-bib-0012","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1038\/nri2800","article-title":"Innate IL-17-producing cells: the sentinels of the immune system","volume":"10","author":"Cua","year":"2010","journal-title":"Nat Rev Immunol"},{"key":"2021121023213119200_cei13445-bib-0013","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1080\/15412550903049124","article-title":"The role of dendritic cells in the pathogenesis of COPD: liaison officers in the front line","volume":"6","author":"Van Pottelberge","year":"2009","journal-title":"COPD"},{"key":"2021121023213119200_cei13445-bib-0014","doi-asserted-by":"crossref","first-page":"1686","DOI":"10.1016\/j.ebiom.2015.09.040","article-title":"IL-22 defect during Streptococcus pneumoniae infection triggers exacerbation of chronic obstructive pulmonary disease","volume":"2","author":"Pichavant","year":"2015","journal-title":"EBioMed"},{"key":"2021121023213119200_cei13445-bib-0015","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1038\/mi.2016.40","article-title":"Interleukin-22 protects against non-typeable Haemophilus influenzae infection: alteration during chronic obstructive pulmonary disease","volume":"10","author":"Sharan","year":"2017","journal-title":"Mucosal Immunol"},{"key":"2021121023213119200_cei13445-bib-0016","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1111\/j.1600-065X.2008.00703.x","article-title":"Th17 cytokines and mucosal immunity","volume":"226","author":"Dubin","year":"2008","journal-title":"Immunol Rev"},{"key":"2021121023213119200_cei13445-bib-0017","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1038\/nri3766","article-title":"The IL-20 subfamily of cytokines\u2013from host defence to tissue homeostasis","volume":"14","author":"Rutz","year":"2014","journal-title":"Nat Rev Immunol"},{"key":"2021121023213119200_cei13445-bib-0018","doi-asserted-by":"crossref","first-page":"7574","DOI":"10.4049\/jimmunol.180.11.7574","article-title":"Administration of a synthetic TLR4 agonist protects mice from pneumonic tularemia","volume":"180","author":"Lembo","year":"2008","journal-title":"J Immunol"},{"key":"2021121023213119200_cei13445-bib-0019","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.drudis.2006.11.007","article-title":"Current and future drugs targeting one class of innate immunity receptors: the Toll-like receptors","volume":"12","author":"Romagne","year":"2007","journal-title":"Drug Discov Today"},{"key":"2021121023213119200_cei13445-bib-0020","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1093\/infdis\/jiu106","article-title":"Activation of Type 3 innate lymphoid cells and interleukin 22 secretion in the lungs during Streptococcus pneumoniae infection","volume":"210","author":"Van Maele","year":"2014","journal-title":"J Infect Dis"},{"key":"2021121023213119200_cei13445-bib-0021","doi-asserted-by":"crossref","first-page":"12487","DOI":"10.1073\/pnas.0605200103","article-title":"Involvement of Toll-like receptor 5 in the recognition of flagellated bacteria","volume":"103","author":"Feuillet","year":"2006","journal-title":"Proc Natl Acad Sci USA"},{"key":"2021121023213119200_cei13445-bib-0022","doi-asserted-by":"crossref","first-page":"1587","DOI":"10.1002\/eji.200838907","article-title":"Radioresistant cells expressing TLR5 control the respiratory epithelium's innate immune responses to flagellin","volume":"39","author":"Janot","year":"2009","journal-title":"Eur J Immunol"},{"key":"2021121023213119200_cei13445-bib-0023","doi-asserted-by":"crossref","first-page":"6064","DOI":"10.1128\/AAC.01210-15","article-title":"A Toll-like receptor 5 agonist improves the efficacy of antibiotics in treatment of primary and influenza virus-associated pneumococcal mouse infections","volume":"59","author":"Porte","year":"2015","journal-title":"Antimicrob Agents Chemother"},{"key":"2021121023213119200_cei13445-bib-0024","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1093\/infdis\/jis413","article-title":"Key role for respiratory CD103(+) dendritic cells, IFN-gamma, and IL-17 in protection against Streptococcus pneumoniae infection in response to alpha-galactosylceramide","volume":"206","author":"Ivanov","year":"2012","journal-title":"J Infect Dis"},{"key":"2021121023213119200_cei13445-bib-0025","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1016\/j.imbio.2011.10.012","article-title":"Protection against Streptococcus pneumoniae serotype 1 acute infection shows a signature of Th17- and IFN-gamma-mediated immunity","volume":"217","author":"Marques","year":"2012","journal-title":"Immunobiology"},{"key":"2021121023213119200_cei13445-bib-0026","doi-asserted-by":"crossref","first-page":"1196","DOI":"10.1128\/IAI.01403-06","article-title":"Interleukin-12 promotes gamma interferon-dependent neutrophil recruitment in the lung and improves protection against respiratory Streptococcus pneumoniae infection","volume":"75","author":"Sun","year":"2007","journal-title":"Infect Immun"},{"key":"2021121023213119200_cei13445-bib-0027","doi-asserted-by":"crossref","first-page":"2036","DOI":"10.4049\/jimmunol.181.3.2036","article-title":"Deletion of flagellin's hypervariable region abrogates antibody-mediated neutralization and systemic activation of TLR5-dependent immunity","volume":"181","author":"Nempont","year":"2008","journal-title":"J Immunol"},{"key":"2021121023213119200_cei13445-bib-0028","article-title":"Global initiative for chronic obstructive lung disease: the changes made","volume":"11","author":"Patel","year":"2019","journal-title":"Cureus"},{"key":"2021121023213119200_cei13445-bib-0029","doi-asserted-by":"crossref","first-page":"3331","DOI":"10.1016\/j.vaccine.2015.05.022","article-title":"Indirect Toll-like receptor 5-mediated activation of conventional dendritic cells promotes the mucosal adjuvant activity of flagellin in the respiratory tract","volume":"33","author":"Fougeron","year":"2015","journal-title":"Vaccine"},{"key":"2021121023213119200_cei13445-bib-0030","doi-asserted-by":"crossref","first-page":"2423","DOI":"10.1038\/jid.2010.158","article-title":"The antimicrobial heterodimer S100A8\/S100A9 (calprotectin) is upregulated by bacterial flagellin in human epidermal keratinocytes","volume":"130","author":"Abtin","year":"2010","journal-title":"J Invest Dermatol"},{"key":"2021121023213119200_cei13445-bib-0031","doi-asserted-by":"crossref","first-page":"1429","DOI":"10.1038\/mi.2016.24","article-title":"Interleukin-22 regulates antimicrobial peptide expression and keratinocyte differentiation to control Staphylococcus aureus colonization of the nasal mucosa","volume":"9","author":"Mulcahy","year":"2016","journal-title":"Mucosal Immunol"},{"key":"2021121023213119200_cei13445-bib-0032","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1164\/rccm.200808-1306OC","article-title":"Bacteria challenge in smoke-exposed mice exacerbates inflammation and skews the inflammatory profile","volume":"179","author":"Gaschler","year":"2009","journal-title":"Am J Respir Crit Care Med"},{"key":"2021121023213119200_cei13445-bib-0033","doi-asserted-by":"crossref","first-page":"4226","DOI":"10.1128\/IAI.00224-10","article-title":"Mucosal administration of flagellin protects mice from Streptococcus pneumoniae lung infection","volume":"78","author":"Munoz","year":"2010","journal-title":"Infect Immun"},{"key":"2021121023213119200_cei13445-bib-0034","doi-asserted-by":"crossref","first-page":"1177","DOI":"10.4049\/jimmunol.1000115","article-title":"TLR5 signaling stimulates the innate production of IL-17 and IL-22 by CD3(neg)CD127+ immune cells in spleen and mucosa","volume":"185","author":"Van Maele","year":"2010","journal-title":"J Immunol"},{"key":"2021121023213119200_cei13445-bib-0035","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1038\/mi.2013.66","article-title":"Airway structural cells regulate TLR5-mediated mucosal adjuvant activity","volume":"7","author":"Van Maele","year":"2014","journal-title":"Mucosal Immunol"},{"key":"2021121023213119200_cei13445-bib-0036","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1358\/dnp.2002.15.7.840075","article-title":"The flagellin\u2013TLR5 axis: therapeutic opportunities","volume":"15","author":"Liaudet","year":"2002","journal-title":"Drug News Perspect"},{"key":"2021121023213119200_cei13445-bib-0037","doi-asserted-by":"crossref","first-page":"3366","DOI":"10.4049\/jimmunol.180.5.3366","article-title":"Blockade of antimicrobial proteins S100A8 and S100A9 inhibits phagocyte migration to the alveoli in streptococcal pneumonia","volume":"180","author":"Raquil","year":"2008","journal-title":"J Immunol"},{"key":"2021121023213119200_cei13445-bib-0038","doi-asserted-by":"crossref","first-page":"1298","DOI":"10.3389\/fimmu.2018.01298","article-title":"S100A8\/A9 in Inflammation","volume":"9","author":"Wang","year":"2018","journal-title":"Front Immunol"},{"key":"2021121023213119200_cei13445-bib-0039","doi-asserted-by":"crossref","DOI":"10.1128\/IAI.00706-17","article-title":"Interleukin-22 immunotherapy during severe influenza enhances lung tissue integrity and reduces secondary bacterial systemic invasion","volume":"86","author":"Barthelemy","year":"2018","journal-title":"Infect Immun"},{"key":"2021121023213119200_cei13445-bib-0040","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1186\/s12931-016-0408-6","article-title":"Cigarette smoke alters the ability of human dendritic cells to promote anti-Streptococcus pneumoniae Th17 response","volume":"17","author":"Le Rouzic","year":"2016","journal-title":"Respir Res"},{"key":"2021121023213119200_cei13445-bib-0041","doi-asserted-by":"crossref","first-page":"723","DOI":"10.3389\/fimmu.2019.00723","article-title":"Therapeutic synergy between antibiotics and pulmonary Toll-Like receptor 5 stimulation in antibiotic-sensitive or -resistant pneumonia","volume":"10","author":"Matarazzo","year":"2019","journal-title":"Front Immunol"}],"container-title":["Clinical and Experimental Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fcei.13445","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cei.13445","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/cei.13445","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/cei\/article-pdf\/201\/2\/171\/41636142\/cei13445.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/cei\/article-pdf\/201\/2\/171\/41636142\/cei13445.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,1,1]],"date-time":"2022-01-01T16:28:55Z","timestamp":1641054535000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/cei\/article\/201\/2\/171\/6403158"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,5,17]]},"references-count":41,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2020,5,17]]},"published-print":{"date-parts":[[2020,7,17]]}},"URL":"https:\/\/doi.org\/10.1111\/cei.13445","relation":{},"ISSN":["0009-9104","1365-2249"],"issn-type":[{"value":"0009-9104","type":"print"},{"value":"1365-2249","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2020,8]]},"published":{"date-parts":[[2020,5,17]]}}}