title: Overlapping and independent contributions of MMP2 and MMP9 to lung allergic inflammatory cell egression through decreased CC chemokines.
abstract: The mechanisms that initiate allergic lung inflammation are relevant to expression of diseases such as asthma, but the factors underlying resolution of inflammation are equally important. Previously, we demonstrated the importance of matrix metalloproteinase 2 (MMP2) for airway egression of lung eosinophils, a critical anti-inflammatory mechanism without which mice are rendered highly susceptible to lethal asphyxiation. Here we show that leukocyte MMP9 is the dominant airway MMP controlling inflammatory cell egression. The allergic lung phenotype of MMP9-/- mice was similar to WT and was not altered by concomitant deletion of the MMP2 gene (double knockout; dko). However, inflammatory cells accumulated aberrantly in the lungs of allergen-challenged MMP9-/- and dko mice and fewer eosinophils and neutrophils were present in bronchoalveolar lavage. These aberrant cellular trafficking patterns were explained by disruption of transepithelial chemokine gradients, in MMP2-/- mice affecting only eotaxin (CCL11), but in MMP9-/- and dko mice involving eotaxin, MARC (CCL7), and TARC (CCL17). Thus, by establishing multiple transepithelial chemokine gradients, MMP9 is broadly implicated in the resolution of allergic inflammation, an essential protective mechanism that overlaps with a more limited role played by MMP2.
authors.affiliation: Baylor College of Medicine, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: David B
authors.initials: DB
authors.lastname: Corry
authors.forename: Attila
authors.initials: A
authors.lastname: Kiss
authors.forename: Li-Zhen
authors.initials: LZ
authors.lastname: Song
authors.forename: Ling
authors.initials: L
authors.lastname: Song
authors.forename: Jie
authors.initials: J
authors.lastname: Xu
authors.forename: Seung-Hyo
authors.initials: SH
authors.lastname: Lee
authors.forename: Zena
authors.initials: Z
authors.lastname: Werb
authors.forename: Farrah
authors.initials: F
authors.lastname: Kheradmand
mesh_terms: D000818:Animals; D017209:Apoptosis; D001249:Asthma / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D054413:Chemokine CCL11; D054414:Chemokine CCL17; D054410:Chemokine CCL7; D019742:Chemokines, CC / Q000032:analysis / Q000172:deficiency / Q000378:metabolism*; D016207:Cytokines / Q000032:analysis / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D006967:Hypersensitivity; D007249:Inflammation / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007962:Leukocytes; D008168:Lung / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018945:Monocyte Chemoattractant Proteins / Q000032:analysis / Q000378:metabolism
chemical_list: C515457:Ccl11 protein, mouse; C499538:Ccl17 protein, mouse; C515451:Ccl7 protein, mouse; D054413:Chemokine CCL11; D054414:Chemokine CCL17; D054410:Chemokine CCL7; D019742:Chemokines, CC; D016207:Cytokines; D018945:Monocyte Chemoattractant Proteins; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9