Preventing cleavage of Mer promotes efferocytosis and suppresses acute lung injury in bleomycin treated mice

• Published in: Toxicology and applied pharmacology Vol. 263; no. 1; pp. 61 - 72
• Main Authors: Lee, Ye-Ji, Lee, Seung-Hae, Youn, Young-So, Choi, Ji-Yeon, Song, Keung-Sub, Cho, Min-Sun, Kang, Jihee Lee
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 15.08.2012; Elsevier
• Subjects: 60 APPLIED LIFE SCIENCES; ACETATES; Acute Lung Injury - chemically induced; Acute Lung Injury - prevention & control; ADAM Proteins - drug effects; ADAM Proteins - metabolism; ADAM17 Protein; Animals; Antibiotics, Antineoplastic - pharmacology; APOPTOSIS; Apoptosis - drug effects; Apoptotic cell clearance; Biological and medical sciences; BLEOMYCIN; Bleomycin - pharmacology; Blotting, Western; Caspase 3 - metabolism; Caspase 9 - drug effects; CLEARANCE; Dipeptides - pharmacology; DNA Damage - drug effects; ENZYME IMMUNOASSAY; Enzyme-Linked Immunosorbent Assay; GROWTH FACTORS; Hydroxamic Acids - pharmacology; INFLAMMATION; INJURIES; LACTATE DEHYDROGENASE; Lung injury; LUNGS; MACROPHAGES; Male; Medical sciences; Mer receptor tyrosine kinase; MICE; Mice, Inbred C57BL; Phagocytosis - drug effects; Receptor Protein-Tyrosine Kinases - drug effects; Receptor Protein-Tyrosine Kinases - metabolism; Receptor Protein-Tyrosine Kinases - physiology; RECEPTORS; Reverse Transcriptase Polymerase Chain Reaction; TAPI-0; Toxicology; TYROSINE; TAM; Mer receptor tyrosine kinase; PMA; MIP-2; HGF; IL-1β; BAL; LPS; ADAM; LDH; sMer; Apoptotic cell clearance; Bleomycin; TNF-α; PI; TGF-β; TAPI-0; Mer; Gas6; ELISA; Lung injury; Antineoplastic agent; Peptides; Efferocytosis; Clearance; Prevention; Glycopeptide; Cleavage; Protein-tyrosine kinase; Protooncogene; Biological receptor; Lung disease; Enzyme; Respiratory disease; Transferases; Acute; Rodentia; In vitro; Vertebrata; Antibiotic; Mammalia; Treatment; Mouse; Animal; C-Onc gene; Apoptosis
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2012.05.024

Mer receptor tyrosine kinase (Mer) regulates macrophage activation and promotes apoptotic cell clearance. Mer activation is regulated through proteolytic cleavage of the extracellular domain. To determine if membrane-bound Mer is cleaved during bleomycin-induced lung injury, and, if so, how preventing the cleavage of Mer enhances apoptotic cell uptake and down-regulates pulmonary immune responses. During bleomycin-induced acute lung injury in mice, membrane-bound Mer expression decreased, but production of soluble Mer and activity as well as expression of disintegrin and metalloproteinase 17 (ADAM17) were enhanced . Treatment with the ADAM inhibitor TAPI-0 restored Mer expression and diminished soluble Mer production. Furthermore, TAPI-0 increased Mer activation in alveolar macrophages and lung tissue resulting in enhanced apoptotic cell clearance in vivo and ex vivo by alveolar macrophages. Suppression of bleomycin-induced pro-inflammatory mediators, but enhancement of hepatocyte growth factor induction were seen after TAPI-0 treatment. Additional bleomycin-induced inflammatory responses reduced by TAPI-0 treatment included inflammatory cell recruitment into the lungs, levels of total protein and lactate dehydrogenase activity in bronchoalveolar lavage fluid, as well as caspase-3 and caspase-9 activity and alveolar epithelial cell apoptosis in lung tissue. Importantly, the effects of TAPI-0 on bleomycin-induced inflammation and apoptosis were reversed by coadministration of specific Mer-neutralizing antibodies. These findings suggest that restored membrane-bound Mer expression by TAPI-0 treatment may help resolve lung inflammation and apoptosis after bleomycin treatment. ►Mer expression is restored by TAPI-0 treatment in bleomycin-stimulated lung. ►Mer signaling is enhanced by TAPI-0 treatment in bleomycin-stimulated lung. ►TAPI-0 enhances efferocytosis and promotes resolution of lung injury.