Cigarette smoke augments CSF3 expression in neutrophils to compromise alveolar-capillary barrier function during influenza infection.

Autor:	McGrath JJC; McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada.; Dept of Medicine, McMaster University, Hamilton, ON, Canada.; Authors contributed equally., Vanderstocken G; McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada.; Dept of Medicine, McMaster University, Hamilton, ON, Canada.; Authors contributed equally., Dvorkin-Gheva A; McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada.; Dept of Medicine, McMaster University, Hamilton, ON, Canada., Cass SP; McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada.; Dept of Medicine, McMaster University, Hamilton, ON, Canada., Afkhami S; McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada.; Dept of Medicine, McMaster University, Hamilton, ON, Canada., Fantauzzi MF; McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada.; Dept of Medicine, McMaster University, Hamilton, ON, Canada., Thayaparan D; McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada.; Dept of Medicine, McMaster University, Hamilton, ON, Canada., Reihani A; Firestone Institute for Respiratory Health, St Joseph's Healthcare Hamilton, Hamilton, ON, Canada.; The Research Institute of St Joe's Hamilton, Hamilton, ON, Canada., Wang P; McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada.; Dept of Medicine, McMaster University, Hamilton, ON, Canada., Beaulieu A; McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada.; Dept of Medicine, McMaster University, Hamilton, ON, Canada., Shen P; McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada.; Dept of Medicine, McMaster University, Hamilton, ON, Canada., Morissette M; Dept of Medicine, Université Laval, Quebec City, QC, Canada.; Quebec Heart and Lung Institute, Université Laval, Quebec City, QC, Canada., Jiménez-Saiz R; Dept of Medicine, McMaster University, Hamilton, ON, Canada.; Dept of Immunology, Instituto de Investigación Sanitaria Hospital Universitario de La Princesa, Madrid, Spain.; Dept of Immunology and Oncology, Centro Nacional de Biotecnología (CNB)-CSIC, Madrid, Spain.; Faculty of Experimental Sciences, Universidad Francisco de Vitoria, Madrid, Spain., Revill SD; Firestone Institute for Respiratory Health, St Joseph's Healthcare Hamilton, Hamilton, ON, Canada.; The Research Institute of St Joe's Hamilton, Hamilton, ON, Canada., Tabuchi A; Keenan Research Centre for Biomedical Science, St Michael's Hospital, Toronto, ON, Canada., Zabini D; Keenan Research Centre for Biomedical Science, St Michael's Hospital, Toronto, ON, Canada., Lee WL; Keenan Research Centre for Biomedical Science, St Michael's Hospital, Toronto, ON, Canada., Richards CD; McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada.; Dept of Medicine, McMaster University, Hamilton, ON, Canada., Miller MS; McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada.; Dept of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada.; Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, ON, Canada., Ask K; McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada.; Dept of Medicine, McMaster University, Hamilton, ON, Canada.; Firestone Institute for Respiratory Health, St Joseph's Healthcare Hamilton, Hamilton, ON, Canada., Kuebler WM; Keenan Research Centre for Biomedical Science, St Michael's Hospital, Toronto, ON, Canada.; Institute of Physiology, Charité Universitätsmedizin Berlin, Berlin, Germany., Simpson JA; Dept of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada., Stämpfli MR; McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada stampfli@mcmaster.ca.; Dept of Medicine, McMaster University, Hamilton, ON, Canada.; Firestone Institute for Respiratory Health, St Joseph's Healthcare Hamilton, Hamilton, ON, Canada.
Jazyk:	angličtina
Zdroj:	The European respiratory journal [Eur Respir J] 2022 Aug 25; Vol. 60 (2). Date of Electronic Publication: 2022 Aug 25 (Print Publication: 2022).
DOI:	10.1183/13993003.02049-2021
Abstrakt:	Background: Cigarette smokers are at increased risk of acquiring influenza, developing severe disease and requiring hospitalisation/intensive care unit admission following infection. However, immune mechanisms underlying this predisposition are incompletely understood, and therapeutic strategies for influenza are limited. Methods: We used a mouse model of concurrent cigarette smoke exposure and H1N1 influenza infection, colony-stimulating factor (CSF)3 supplementation/receptor (CSF3R) blockade and single-cell RNA sequencing (scRNAseq) to investigate this relationship. Results: Cigarette smoke exposure exacerbated features of viral pneumonia such as oedema, hypoxaemia and pulmonary neutrophilia. Smoke-exposed infected mice demonstrated an increase in viral (v)RNA, but not replication-competent viral particles, relative to infection-only controls. Interstitial rather than airspace neutrophilia positively predicted morbidity in smoke-exposed infected mice. Screening of pulmonary cytokines using a novel dysregulation score identified an exacerbated expression of CSF3 and interleukin-6 in the context of smoke exposure and influenza. Recombinant (r)CSF3 supplementation during influenza aggravated morbidity, hypothermia and oedema, while anti-CSF3R treatment of smoke-exposed infected mice improved alveolar-capillary barrier function. scRNAseq delineated a shift in the distribution of Csf3 + cells towards neutrophils in the context of cigarette smoke and influenza. However, although smoke-exposed lungs were enriched for infected, highly activated neutrophils, gene signatures of these cells largely reflected an exacerbated form of typical influenza with select unique regulatory features. Conclusion: This work provides novel insight into the mechanisms by which cigarette smoke exacerbates influenza infection, unveiling potential therapeutic targets ( e.g. excess vRNA accumulation, oedematous CSF3R signalling) for use in this context, and potential limitations for clinical rCSF3 therapy during viral infectious disease. Competing Interests: Conflict of interest: M.S. Miller reports consulting fees for scientific advisory board participation from Seqirus and Medicago (influenza vaccines); lecture honoraria for lunch-and-learn on COVID-19 vaccines from Boehringer-Ingelheim; outside the submitted work. K. Ask reports grants from Alkermes, Prometic, GSK, Canadian Institute for Health Research, Pharmaxis, Indalo, Unity Biotechnology, Canadian Pulmonary Fibrosis Association, Collaborative Health Research Projects, Pieris Pharmaceuticals, Bold Therapeutics, Pliant, CSL Behring and Boehringer Ingelheim; lecture honoraria from Boehringer Ingelheim; travel support from Boehringer Ingelheim; outside the submitted work. W.M. Kuebler reports grant-in-aid from Canadian Institutes of Health Research (CIHR), during the course of the present study; grants-in-aid from German Research Foundation (DFG), German Ministry for Research and Education (BMBF), Berlin Institute of Health (BIH), German Centre for Cardiovascular Research (DZHK); outside the submitted work. M.R. Stämpfli reports support for the present manuscript from Canadian Institutes of Health Research; grants from RespiVert Pharmaceuticals, Canadian Heart and Stroke Foundation, and Ontario Thoracic Society; consulting fees from Boehringer Ingelheim; lecture honoraria from AstraZeneca; MTA for monoclonal antibody to block G-CSF from CSL Behring and is employed by CSL Behring since January 2020; outside the submitted work. All other authors have nothing to disclose. (Copyright ©The authors 2022. For reproduction rights and permissions contact permissions@ersnet.org.)
Databáze:	MEDLINE
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