title: Matrix metalloproteinases contribute to the regulation of chemokine expression and pulmonary inflammation in Cryptococcus infection.
abstract: Matrix metalloproteinases (MMPs) are a family of extracellular proteases that play roles in regulating the immune response in inflammatory processes. Previous studies indicated that different MMPs were involved in the host defence and tissue damage in response to different pathogens. However, the contributions of MMPs during Cryptococcus infection have not been addressed clearly. Here, we examined the expression and activity of MMPs during Cryptococcus infection. Among MMP family members, we found significant increases of MMP-3 and MMP-12 mRNA levels and MMP12 zymographic activities in response to C. neoformans but not C. gattii infection. The expression of MMP12 was induced in RAW cells after C. neoformans treatment and in alveolar macrophages purified from C. neoformans-infected mice. Interestingly, administration of MMP inhibitor GM6001 into C. neoformans-infected mice resulted in a significantly increased pulmonary fungal burden with attenuated inflammatory cell infiltration. Corresponding to this finding, the expression of the macrophage- and neutrophil-attracting chemokines CCL2 and CXCL1 was inhibited in the GM6001-treated group and MMP12 levels were found to be correlated strongly with CCL2 mRNA expression. Thus, our data suggest that the induction of MMPs by C. neoformans infection potentiates inflammatory cell infiltration by modulating pulmonary chemokines, thereby promoting effective host immunity to pulmonary Cryptococcus infection.
authors.affiliation: Department of Medical Technology, Faculty of Allied Health Sciences.|Graduate Program in Biomedical Science, Faculty of Allied Health Sciences, Thammasat University, Pathumthani, Thailand.
authors.forename: O
authors.initials: O
authors.lastname: Supasorn
authors.affiliation: Graduate Program in Medical Technology, Faculty of Allied Health Sciences.
authors.forename: N
authors.initials: N
authors.lastname: Sringkarin
authors.affiliation: Graduate Program in Biomedical Science, Faculty of Allied Health Sciences, Thammasat University, Pathumthani, Thailand.
authors.forename: P
authors.initials: P
authors.lastname: Srimanote
authors.affiliation: Department of Medical Technology, Faculty of Allied Health Sciences.|Graduate Program in Medical Technology, Faculty of Allied Health Sciences.
authors.forename: P
authors.initials: P
authors.lastname: Angkasekwinai
mesh_terms: D000818:Animals; D018932:Chemokine CCL2 / Q000235:genetics / Q000276:immunology; D054360:Chemokine CXCL1 / Q000235:genetics / Q000276:immunology; D018925:Chemokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D003453:Cryptococcosis / Q000201:enzymology* / Q000276:immunology* / Q000382:microbiology; D056285:Cryptococcus gattii / Q000276:immunology; D003455:Cryptococcus neoformans / Q000276:immunology / Q000472:pathogenicity; D004151:Dipeptides / Q000008:administration & dosage; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D053508:Matrix Metalloproteinase 12 / Q000235:genetics / Q000276:immunology; D019278:Matrix Metalloproteinase 3 / Q000235:genetics / Q000276:immunology; D061965:Matrix Metalloproteinase Inhibitors / Q000008:administration & dosage; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D011014:Pneumonia / Q000201:enzymology / Q000276:immunology* / Q000382:microbiology; D000067996:RAW 264.7 Cells
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D054360:Chemokine CXCL1; D018925:Chemokines; C475895:Cxcl1 protein, mouse; D004151:Dipeptides; D061965:Matrix Metalloproteinase Inhibitors; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D020782:Matrix Metalloproteinases; D019278:Matrix Metalloproteinase 3; C511769:Mmp3 protein, mouse; D053508:Matrix Metalloproteinase 12; C000602031:matrix metallopeptidase 12, mouse
keywords: Cryptococcus infection; MMP-12; pulmonary inflammation