MMP-8 deficiency increases TLR/RAGE ligands S100A8 and S100A9 and exacerbates lung inflammation during endotoxemia

• Published in: PloS one Vol. 7; no. 6; p. e39940
• Main Authors: González-López, Adrián, Aguirre, Alina, López-Alonso, Inés, Amado, Laura, Astudillo, Aurora, Fernández-García, María Soledad, Suárez, María F, Batalla-Solís, Estefanía, Colado, Enrique, Albaiceta, Guillermo M
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 29.06.2012; Public Library of Science (PLoS)
• Subjects: Analysis; Animals; Biology; Calgranulin A - metabolism; Calgranulin B - metabolism; Chemokines; Endotoxemia; Endotoxemia - complications; Endotoxemia - enzymology; Endotoxemia - immunology; Endotoxemia - pathology; Genotype; Genotypes; Hostages; Infiltration; Inflammation; Inflammatory response; Leukocytes (neutrophilic); Ligands; Lipopolysaccharides; Lipopolysaccharides - pharmacology; Lung - drug effects; Lung - microbiology; Lung - pathology; Lungs; Matrix metalloproteinase; Matrix Metalloproteinase 2 - metabolism; Matrix Metalloproteinase 8 - deficiency; Matrix Metalloproteinase 8 - metabolism; Matrix Metalloproteinase 9 - metabolism; Medicine; Metalloproteinase; Mice; Mice, Inbred C57BL; Neutrophil collagenase; Neutrophils; NF-kappa B - metabolism; NF-κB protein; Ostomy; Pneumonia; Pneumonia - complications; Pneumonia - enzymology; Pneumonia - immunology; Pneumonia - pathology; Proteins; Proteomics; Receptor for Advanced Glycation End Products; Receptors, Immunologic - metabolism; Respiratory distress syndrome; Rodents; Sepsis; Signal Transduction - drug effects; Spleen; Toll-Like Receptors - metabolism; Spain
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0039940

Matrix metalloproteinase-8, released mainly from neutrophils, is a critical regulator of the inflammatory response by its ability to cleave multiple mediators. Herein, we report the results of a model of endotoxemia after intraperitoneal LPS injection in mice lacking MMP-8 and their wildtype counterparts. Control, saline-treated animals showed no differences between genotypes. However, there was an increased lung inflammatory response, with a prominent neutrophilic infiltration in mutant animals after LPS treatment. Using a proteomic approach, we identify alarmins S100A8 and S100A9 as two of the main differences between genotypes. Mice lacking MMP-8 showed a significant increase in these two molecules in lung homogenates, but not in spleen and serum. Mice lacking MMP-8 also showed an increase in MIP-1α levels and a marked activation of the non-canonical NF-κB pathway, with no differences in CXC-chemokines such as MIP-2 or LIX. These results show that MMP-8 can modulate the levels of S100A8 and S100A9 and its absence promotes the lung inflammatory response during endotoxemia.