MMP-25 Metalloprotease Regulates Innate Immune Response through NF-κB Signaling.
Matrix metalloproteases (MMPs) regulate innate immunity acting over proinflammatory cytokines, chemokines, and other immune-related proteins. MMP-25 (membrane-type 6-MMP) is a membrane-bound enzyme predominantly expressed in leukocytes whose biological function has remained largely unknown. We have generated Mmp25-deficient mice to elucidate the in vivo function of this protease. These mutant mice are viable and fertile and do not show any spontaneous phenotype. However, Mmp25-null mice exhibit a defective innate immune response characterized by low sensitivity to bacterial LPS, hypergammaglobulinemia, and reduced secretion of proinflammatory molecules. Moreover, these immune defects can be tracked to a defective NF-κB activation observed in Mmp25-deficient leukocytes. Globally, our findings provide new mechanistic insights into innate immunity through the activity of MMP-25, suggesting that this proteinase could be a potential therapeutic target for immune-related diseases.
Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, 33006 Oviedo, Spain;
Clara
C
Soria-Valles
Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, 33006 Oviedo, Spain;
Ana
A
Gutiérrez-Fernández
Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, 33006 Oviedo, Spain;
Fernando G
FG
Osorio
Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, 33006 Oviedo, Spain;
Dido
0000-0001-7869-838X
D
Carrero
Institute for Cancer Genetics, Columbia University, New York, NY 10032;
Adolfo A
AA
Ferrando
Servivio de Hematología, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain;
Enrique
0000-0001-8675-8207
E
Colado
Servicio de Anatomía Patológica, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain;
M Soledad
MS
Fernández-García
Laboratorio de Proteómica Cardiovascular, Centro Nacional de Investigaciones Cardiovasculares, 28029 Madrid, Spain; and.
Elena
0000-0003-0852-7520
E
Bonzon-Kulichenko
Laboratorio de Proteómica Cardiovascular, Centro Nacional de Investigaciones Cardiovasculares, 28029 Madrid, Spain; and.
Jesús
0000-0003-1461-5092
J
Vázquez
Área de Fisiología, Departamento de Biología Funcional, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, 33006 Oviedo, Spain.
Antonio
A
Fueyo
Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, 33006 Oviedo, Spain; clo@uniovi.es.
Carlos
C
López-Otín
D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D006942:Hypergammaglobulinemia / Q000276:immunology*; D007113:Immunity, Innate / Q000235:genetics; D018836:Inflammation Mediators / Q000378:metabolism; D007962:Leukocytes / Q000276:immunology*; D008070:Lipopolysaccharides / Q000276:immunology; D053504:Matrix Metalloproteinases, Membrane-Associated / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D011485:Protein Binding; D015398:Signal Transduction
D016207:Cytokines; D058851:GPI-Linked Proteins; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D016328:NF-kappa B; D053504:Matrix Metalloproteinases, Membrane-Associated; C403928:matrix metalloproteinase 25