Leukocyte ADAM17 regulates acute pulmonary inflammation

• Published in: PloS one Vol. 6; no. 5; p. e19938
• Main Authors: Arndt, Patrick G, Strahan, Brian, Wang, Yue, Long, Chunmei, Horiuchi, Keisuke, Walcheck, Bruce
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 16.05.2011; Public Library of Science (PLoS)
• Subjects: Acute Disease; ADAM Proteins - immunology; ADAM17 Protein; Alveoli; Animals; B cells; Biology; Bone marrow; Bone surgery; Cell surface; Chemokine CXCL1; Chemokine CXCL5; Chemokines; Critical care; Dendritic cells; Gene expression; Infiltration; Inflammation; Inflammatory bowel disease; Inhalation; Interleukin 6; Internal medicine; L-Selectin; Leukocytes; Leukocytes - enzymology; Leukocytes - immunology; Lipopolysaccharides; Lipopolysaccharides - pharmacology; Lung - chemistry; Lung - immunology; Lungs; Medicine; Mice; Mice, Knockout; Neutrophil Infiltration; Neutrophils; Pharmacology; Pneumonia - etiology; Pneumonia - immunology; Proteases; Proteins; Recruitment; Respiration; Respiratory tract; Respiratory tract diseases; Rodents; Shedding; Substrates; Tumor necrosis factor; Tumor Necrosis Factor-alpha; Tumor necrosis factor-α; United States > US; Minnesota
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0019938

The transmembrane protease ADAM17 regulates the release and density of various leukocyte cell surface proteins that modulate inflammation, including L-selectin, TNF-α, and IL-6R. At this time, its in vivo substrates and role in pulmonary inflammation have not been directly examined. Using conditional ADAM17 knock-out mice, we investigated leukocyte ADAM17 in acute lung inflammation. Alveolar TNF-α levels were significantly reduced (>95%) in ADAM17-null mice following LPS administration, as was the shedding of L-selectin, a neutrophil-expressed adhesion molecule. Alveolar IL-6R levels, however, were reduced by only ≈25% in ADAM17-null mice, indicating that ADAM17 is not its primary sheddase in our model. Neutrophil infiltration into the alveolar compartment is a key event in the pathophysiology of acute airway inflammation. Following LPS inhalation, alveolar neutrophil levels and lung inflammation in ADAM17-null mice were overall reduced when compared to control mice. Interestingly, however, neutrophil recruitment to the alveolar compartment occurred earlier in ADAM17-null mice after exposure to LPS. This decrease in alveolar neutrophil recruitment in ADAM17-null mice was accompanied by significantly diminished alveolar levels of the neutrophil-tropic chemokines CXCL1 and CXCL5. Altogether, our study suggests that leukocyte ADAM17 promotes inflammation in the lung, and thus this sheddase may be a potential target in the design of pharmacologic therapies for acute lung injury.