Elastase-mediated phosphatidylserine receptor cleavage impairs apoptotic cell clearance in cystic fibrosis and bronchiectasis
R. William Vandivier, … , Frank J. Accurso, Peter M. Henson
R. William Vandivier, … , Frank J. Accurso, Peter M. Henson
Published March 1, 2002
Citation Information: J Clin Invest. 2002;109(5):661-670. https://doi.org/10.1172/JCI13572.
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Elastase-mediated phosphatidylserine receptor cleavage impairs apoptotic cell clearance in cystic fibrosis and bronchiectasis

Abstract

Cystic fibrosis is characterized by an early and sustained influx of inflammatory cells into the airways and by release of proteases. Resolution of inflammation is normally associated with the orderly removal of dying apoptotic inflammatory cells through cell recognition receptors, such as the phosphatidylserine receptor, CD36, and αv integrins. Accordingly, removal of apoptotic inflammatory cells may be impaired in persistent inflammatory responses such as that seen in cystic fibrosis airways. Examination of sputa from cystic fibrosis and non–cystic fibrosis bronchiectasis patients demonstrated an abundance of apoptotic cells, in excess of that seen in patients with chronic bronchitis. In vitro, cystic fibrosis and bronchiectasis airway fluid directly inhibited apoptotic cell removal by alveolar macrophages in a neutrophil elastase-dependent manner, suggesting that elastase may impair apoptotic cell clearance in vivo. Flow cytometry demonstrated that neutrophil elastase cleaved the phosphatidylserine receptor, but not CD36 or CD32 (FcγRII). Cleavage of the phosphatidylserine receptor by neutrophil elastase specifically disrupted phagocytosis of apoptotic cells, implying a potential mechanism for delayed apoptotic cell clearance in vivo. Therefore, defective airway clearance of apoptotic cells in cystic fibrosis and bronchiectasis may be due to elastase-mediated cleavage of phosphatidylserine receptor on phagocytes and may contribute to ongoing airway inflammation.

Authors

R. William Vandivier, Valerie A. Fadok, Peter R. Hoffmann, Donna L. Bratton, Churee Penvari, Kevin K. Brown, Joseph D. Brain, Frank J. Accurso, Peter M. Henson

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Figure 2

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CF sol inhibits HMDM ingestion of apoptotic but not IgG-opsonized Jurkat...
CF sol inhibits HMDM ingestion of apoptotic but not IgG-opsonized Jurkat cells in an elastase-dependent manner. (a) HMDMs were cocultured with apoptotic, opsonized, or viable Jurkat cells in the presence or absence of 10% CF sol. The mean phagocytic index as percentage of control ± SEM is shown for three replicates per group. Control mean phagocytic index: 28.6 ± 4.4. *Significantly different from apoptotic Jurkat cells pretreated with media (P < 0.05). (b) HMDMs were cocultured with apoptotic Jurkat cells in the presence of media (Control), 10% CF sol, 10% CF sol plus DMP777 (100 μM), 10% CF sol plus SJ527 (100 μM), or 10% CF sol plus methyl cellulose (MC). The mean phagocytic index as percentage of control ± SEM is shown for three to five replicates per group. Control mean phagocytic index: 52.8 ± 10.2. *Significantly different from control (P < 0.05). (c) HMDMs, apoptotic Jurkat cells, or both were pretreated for 30 minutes with media (Control), 10% CF sol, 10% CF sol plus DMP777 (20 μM), or DMP777 (20 μM) alone prior to coculture. Following pretreatment, coculture was done in the presence of DMP777 (20 μM) to prevent carryover of elastase activity. The mean phagocytic index as percentage of control ± SEM is shown for three replicates per group. Control mean phagocytic index: 51.4 ± 6.0. *Significantly different from control (P < 0.05). **Significantly different from 10% CF sol-pretreated HMDMs (P < 0.05). ***Significantly different from 10% CF sol-pretreated HMDMs and apoptotic Jurkat cells (P < 0.05).