期刊
JOURNAL OF CYSTIC FIBROSIS
卷 21, 期 6, 页码 967-976出版社
ELSEVIER
DOI: 10.1016/j.jcf.2022.06.001
关键词
Cystic fibrosis; Bronchiectasis; Checkpoint inhibition; Elastase; Matrix metalloproteinase; Immunotherapy
资金
- National Institutes of Health (NIH, USA) [R01HL126603]
- Dutch CF foundation (NCFS-HIT-CF)
- US Cystic Fibrosis Foundation [MCCART15R0]
- UAB Research Development Program Fellowship - US CFF [ROWE19R0]
- CFF Postdoc-to-Faculty Award [MARGAR21F5]
- National Health and Medical Research Council (NHMRC
- Australia) [1142505]
- Peter Doherty Fellowship [1141479]
- Western Australian Department of Health Merit Award
- National Science Foundation (NSF, USA) [CCF1552784]
- ISAC Marylou Ingram Scholarship
- German Ministry for Education and Research [FKZ 82DZL00401, FKZ 82DZL004A1]
- German Research Foundation [SFBTR84TP B08]
- Einstein Foundation Berlin [EP-2017393]
- German Cystic Fibrosis Association Mukoviszidose e. V. [1605]
- Heidelberg Research Center for Molecular Medicine Career Development Fellowship
- NHMRC
- NIH
- US Cystic Fibrosis Foundation Therapeutics
- Cystic Fibrosis Australia
- CF@LANTA Research Development Program Pilot Fund - US Cystic Fibrosis Foundation [MCCART15R0]
This study found that upregulation of PD-1 is associated with airway macrophage exhaustion, neutrophil takeover, infection, and structural damage in children with cystic fibrosis.
Background: Macrophages are the major resident immune cells in human airways coordinating responses to infection and injury. In cystic fibrosis (CF), neutrophils are recruited to the airways shortly after birth, and actively exocytose damaging enzymes prior to chronic infection, suggesting a potential defect in macrophage immunomodulatory function. Signaling through the exhaustion marker programmed death protein 1 (PD-1) controls macrophage function in cancer, sepsis, and airway infection. Therefore, we sought to identify potential associations between macrophage PD-1 and markers of airway disease in children with CF. Methods: Blood and bronchoalveolar lavage fluid (BALF) were collected from 45 children with CF aged 3 to 62 months and structural lung damage was quantified by computed tomography. The phenotype of airway leukocytes was assessed by flow cytometry, while the release of enzymes and immunomodulatory mediators by molecular assays. Results: Airway macrophage PD-1 expression correlated positively with structural lung damage, neutrophilic inflammation, and infection. Interestingly, even in the absence of detectable infection, macrophage PD-1 expression was elevated and correlated with neutrophilic inflammation. In an in vitro model mimicking leukocyte recruitment into CF airways, soluble mediators derived from recruited neutrophils directly induced PD-1 expression on recruited monocytes/macrophages, suggesting a causal link between neutrophilic inflammation and macrophage PD-1 expression in CF. Finally, blockade of PD-1 in a short-term culture of CF BALF leukocytes resulted in improved pathogen clearance. Conclusion: Taken together, these findings suggest that in early CF lung disease, PD-1 upregulation associates with airway macrophage exhaustion, neutrophil takeover, infection, and structural damage. (c) 2022 The Author(s). Published by Elsevier B.V. on behalf of European Cystic Fibrosis Society. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
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