Macrophage PD-1 associates with neutrophilia and reduced bacterial killing in early cystic fibrosis airway disease

• Published in: Journal of cystic fibrosis Vol. 21; no. 6; pp. 967 - 976
• Main Authors: Margaroli, Camilla, Horati, Hamed, Garratt, Luke W., Giacalone, Vincent D., Schofield, Craig, Dittrich, A. Susanne, Rosenow, Tim, Dobosh, Brian S., Lim, Hong S., Frey, Dario L., Veltman, Mieke, Silva, George L., Brown, Milton R., Schultz, Carsten, Tiddens, Harm A.W.M., Ranganathan, Sarath, Chandler, Joshua D., Qiu, Peng, Peng, Limin, Scholte, Bob J., Mall, Marcus A., Kicic, Anthony, Guglani, Lokesh, Stick, Stephen M., Janssens, Hettie M., Tirouvanziam, Rabindra
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.11.2022
• Subjects: Bacteria - metabolism; Biomarkers - metabolism; Bronchiectasis; Checkpoint inhibition; Child; Cystic Fibrosis; Elastase; Humans; Immunotherapy; Inflammation; Lung; Macrophages; Matrix metalloproteinase; Programmed Cell Death 1 Receptor; Cystic fibrosis; Checkpoint inhibition; Bronchiectasis; Elastase; Matrix metalloproteinase; Immunotherapy
• ISSN: 1569-1993; 1873-5010
• DOI: 10.1016/j.jcf.2022.06.001

•Macrophages are gradually replaced by neutrophils in early CF lung disease•Signaling through the PD-1 pathway is known to inhibit immune cell activation•Macrophage PD-1 expression associates with neutrophilia, infection and lung damage•Neutrophil-derived factors induce PD-1 expression in airway-like monocytes•Blocking PD-1 on patient airway leukocytes improves bacteria killing 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. 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. 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. 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.