Human lung cDC1 drive increased perforin-mediated NK cytotoxicity in chronic obstructive pulmonary disease
| Autor: | Jessica X Rao, Dawit T Mengistu, Lisa McCloskey, Christine M. Freeman, Alexander M Pallazola, M.S. Toma, Valerie R. Stolberg, Maria S Morcos, Jeffrey L. Curtis, Alexandra Tretyakova |
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| Rok vydání: | 2021 |
| Předmět: |
Pulmonary and Respiratory Medicine
Male Physiology Pulmonary disease Granzymes Human lung Pulmonary Disease Chronic Obstructive Physiology (medical) medicine Humans COPD human Cytotoxicity Lung natural killer cells biology business.industry Cytotoxins Perforin Smoking Epithelial Cells Cell Biology Dendritic Cells respiratory system Middle Aged medicine.disease Epithelium In vitro respiratory tract diseases Killer Cells Natural medicine.anatomical_structure Gene Expression Regulation Case-Control Studies Cancer research biology.protein Female business Research Article |
| Zdroj: | American Journal of Physiology-Lung Cellular and Molecular Physiology |
| ISSN: | 1522-1504 |
| Popis: | In chronic obstructive pulmonary disease (COPD), lung natural killer cells (NKs) lyse autologous lung epithelial cells in vitro, but underlying mechanisms and their relationship to epithelial cell apoptosis in vivo are undefined. Although this cytolytic capacity of lung NKs depends on priming by dendritic cells (DCs), whether priming correlates with DC maturation or is limited to a specific DC subset is also unknown. We recruited ever-smokers (≥10 pack-years; n = 96) undergoing clinically indicated lung resections. We analyzed lung NKs for cytotoxic molecule transcripts and for cytotoxicity, which we correlated with in situ detection of activated Caspase-3/7+ airway epithelial cells. To investigate DC priming, we measured lung DC expression of CCR2, CCR7, and CX3CR1 and cocultured peripheral blood NKs with autologous lung DCs, either matured using lipopolysaccharide (LPS) (nonobstructed smokers) or separated into conventional dendritic cell type-1 (cDC1) versus cDC type-2 (cDC2) (COPD). Lung NKs in COPD expressed more perforin ( P < 0.02) and granzyme B ( P < 0.03) transcripts; inhibiting perforin blocked in vitro killing by lung NKs. Cytotoxicity in vitro correlated significantly ( Sr = 0.68, P = 0.0043) with numbers of apoptotic epithelial cells per airway. In nonobstructed smokers, LPS-induced maturation enhanced DC-mediated priming of blood NKs, reflected by greater epithelial cell death. Although CCR7 expression was greater in COPD in both cDC1 ( P < 0.03) and cDC2 ( P = 0.009), only lung cDC1 primed NK killing. Thus, rather than being intrinsic to those with COPD, NK priming is a capacity of human lung DCs that is inducible by recognition of bacterial (and possibly other) danger signals and restricted to the cDC1 subset. |
| Databáze: | OpenAIRE |
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