Elastase-mediated phosphatidylserine receptor cleavage impairs apoptotic cell clearance in cystic fibrosis and bronchiectasis.
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 alpha v 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 (Fc gamma RII). 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.
Vandivier
R William
RW
Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado, USA. vandivierb@njc.org
Fadok
Valerie A
VA
Hoffmann
Peter R
PR
Bratton
Donna L
DL
Penvari
Churee
C
Brown
Kevin K
KK
Brain
Joseph D
JD
Accurso
Frank J
FJ
Henson
Peter M
PM
D000293:Adolescent; D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000502:physiology*; D001987:Bronchiectasis / Q000473:pathology* / Q000503:physiopathology*; D018955:CD36 Antigens / Q000378:metabolism; D003550:Cystic Fibrosis / Q000473:pathology* / Q000503:physiopathology*; D006801:Humans; D066298:In Vitro Techniques; D056484:Jumonji Domain-Containing Histone Demethylases; D019169:Jurkat Cells; D019272:Leukocyte Elastase / Q000502:physiology*; D016676:Macrophages, Alveolar / Q000502:physiology; D008875:Middle Aged; D010587:Phagocytosis; D011956:Receptors, Cell Surface / Q000502:physiology*; D017452:Receptors, IgG / Q000378:metabolism
D018955:CD36 Antigens; D011956:Receptors, Cell Surface; D017452:Receptors, IgG; C408123:phosphatidylserine receptor; C498707:JMJD6 protein, human; D056484:Jumonji Domain-Containing Histone Demethylases; D019272:Leukocyte Elastase