ATP-binding cassette transporter A7 enhances phagocytosis of apoptotic cells and associated ERK signaling in macrophages

The mammalian ATP-binding cassette transporters A1 and A7 (ABCA1 and -A7) show sequence similarity to CED-7, a Caenorhabditis elegans gene that mediates the clearance of apoptotic cells. Using RNA interference or gene targeting, we show that knock down of macrophage ABCA7 but not -A1 results in defective engulfment of apoptotic cells. In response to apoptotic cells, ABCA7 moves to the macrophage cell surface and colocalizes with the low-density lipoprotein receptor–related protein 1 (LRP1) in phagocytic cups. The cell surface localization of ABCA7 and LRP1 is defective in ABCA7-deficient cells. C1q is an opsonin of apoptotic cells that acts via phagocyte LRP1 to induce extracellular signal–regulated kinase (ERK) signaling. We show that ERK signaling is required for phagocytosis of apoptotic cells and that ERK phosphorylation in response to apoptotic cells or C1q is defective in ABCA7-deficient cells. These studies reveal a major role of ABCA7 and not -A1 in the clearance of apoptotic cells and therefore suggest that ABCA7 is an authentic orthologue of CED-7

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

Statins enhance clearance of apoptotic cells through modulation of Rho-GTPases

Borges, Valéria de Matos “Documento produzido em parceria ou por autor vinculado à Fiocruz, mas não consta à informação no documento”.Submitted by Ana Maria Fiscina Sampaio ([email protected]) on 2017-06-28T16:42:57Z No. of bitstreams: 1 Morimoto K Statins enhance....pdf: 58770 bytes, checksum: 9f899477eed2cfc74b16269e07e21020 (MD5)Approved for entry into archive by Ana Maria Fiscina Sampaio ([email protected]) on 2017-06-28T16:53:14Z (GMT) No. of bitstreams: 1 Morimoto K Statins enhance....pdf: 58770 bytes, checksum: 9f899477eed2cfc74b16269e07e21020 (MD5)Made available in DSpace on 2017-06-28T16:53:14Z (GMT). No. of bitstreams: 1 Morimoto K Statins enhance....pdf: 58770 bytes, checksum: 9f899477eed2cfc74b16269e07e21020 (MD5) Previous issue date: 2006-08Pfizer Atorvastatin Research AwardUniversity of Colorado Health Sciences Center. Division of Pulmonary Sciences and Critical Care Medicine. Denver, Colorado / National Jewish Medical and Research Center. Department of Immunology. Denver, ColoradoUniversity of Colorado Health Sciences Center. Division of Pulmonary Sciences and Critical Care Medicine. Denver, Colorado / National Jewish Medical and Research Center. Department of Immunology. Denver, ColoradoUniversity of Colorado Health Sciences Center. Division of Pulmonary Sciences and Critical Care Medicine. Denver, Colorado / National Jewish Medical and Research Center. Department of Immunology. Denver, ColoradoUniversity of Colorado Health Sciences Center. Division of Pulmonary Sciences and Critical Care Medicine. Denver, Colorado / National Jewish Medical and Research Center. Department of Immunology. Denver, ColoradoUniversity of Colorado Health Sciences Center. Division of Pulmonary Sciences and Critical Care Medicine. Denver, Colorado / National Jewish Medical and Research Center. Department of Immunology. Denver, ColoradoUniversity of Colorado Health Sciences Center. Division of Pulmonary Sciences and Critical Care Medicine. Denver, Colorado / National Jewish Medical and Research Center. Department of Immunology. Denver, ColoradoUniversity of Colorado Health Sciences Center. Division of Pulmonary Sciences and Critical Care Medicine. Denver, Colorado / National Jewish Medical and Research Center. Department of Immunology. Denver, ColoradoUniversity of Colorado Health Sciences Center. Division of Pulmonary Sciences and Critical Care Medicine. Denver, Colorado / National Jewish Medical and Research Center. Department of Immunology. Denver, ColoradoUniversity of Colorado Health Sciences Center. Division of Pulmonary Sciences and Critical Care Medicine. Denver, Colorado / National Jewish Medical and Research Center. Department of Immunology. Denver, Colorad

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 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

Bronchoalveolar (BAL) fluid, lung, and serum IL-10 after intratracheal (IT) IL-6 treatment in acute kidney injury (AKI), intraperitoneal (IP) endotoxin, and IT endotoxin.

<p>The anti-inflammatory cytokine IL-10 was determined in the (A) BAL fluid, (B) lung, and (C) serum 4 hours after AKI (indirect lung injury), IP endotoxin (indirect lung injury), and IT endotoxin (direct lung injury) in mice treated with 200 ng of IT IL-6 or IT vehicle (veh) (0.1% BSA) 30 minutes prior to injury (n = 5–7).</p