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Matrix metalloproteinase 12 overexpression in myeloid lineage cells plays a key role in modulating myelopoiesis, immune suppression, and lung tumorigenesis.

ABSTRACT: Matrix metalloproteinase 12 (MMP12) is a macrophage-secreting proteinase. To fully understand the function of MMP12 in myeloid lineage cells, a myeloid-specific c-fms-rtTA/(TetO)?-CMV-MMP12 bitransgenic mouse model was created. In this bitransgenic system, induction of MMP12 abnormally elevated frequencies and numbers of common myeloid progenitor (CMP) and granulocyte/macrophage progenitor (GMP) populations, and decreased the frequency and number of the megakaryocyte/erythrocyte progenitor (MEP) population in the bone marrow (BM). The CD11b(+)/Gr-1(+) immature cell population was systemically increased in multiple organs. Both in vitro and in vivo studies showed an immunosuppressive function on T-cell proliferation and function by CD11b(+)/Gr-1(+) immature cells from MMP12-overexpressing bitransgenic mice. MMP12 directly stimulated lineage-negative (Lin?) progenitor cells to differentiate into CD11b(+)/Gr-1(+) immature cells that showed immunosuppression on T-cell proliferation and function in vitro. Regulatory T cells (Tregs) were increased. In the lung, the concentration of IL-6 was increased, which aberrantly activated oncogenic Stat3 and increased expression of Stat3 downstream genes in epithelial tumor progenitor cells. Spontaneous emphysema and lung adenocarcinoma were sequentially developed after MMP12 overexpression. BM chimeras confirmed that the MMP12-induced myeloid cell autonomous defect led to abnormal myelopoiesis, immune suppression, and lung adenocarcinoma.

SUBMITTER: Qu P

PROVIDER: S-EPMC3099569 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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Matrix metalloproteinase 12 overexpression in myeloid lineage cells plays a key role in modulating myelopoiesis, immune suppression, and lung tumorigenesis.

Qu Peng P Yan Cong C Du Hong H

Blood 20110304 17

Matrix metalloproteinase 12 (MMP12) is a macrophage-secreting proteinase. To fully understand the function of MMP12 in myeloid lineage cells, a myeloid-specific c-fms-rtTA/(TetO)₇-CMV-MMP12 bitransgenic mouse model was created. In this bitransgenic system, induction of MMP12 abnormally elevated frequencies and numbers of common myeloid progenitor (CMP) and granulocyte/macrophage progenitor (GMP) populations, and decreased the frequency and number of the megakaryocyte/erythrocyte progenitor (MEP) ...[more]

PMID: 21378275

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Project description:BACKGROUND: Aortic dissection(AD) is an acute process of large blood vessels characterized by dangerous pathogenic conditions and high disability and high mortality. The pathogenesis of AD remains debated. Matrix metalloproteinase-12 (MMP-12) participates in many pathological processes such as abdominal aortic aneurysm, atherosclerosis, emphysema and cancer. However, this elastase has rarely been assessed in the presence of AD. The aim of the present study was to investigate the expression of MMP-12 in aortic tissue so as to offer a better understanding of the possible mechanisms of AD. METHODS: The protein expression levels of MMP-12 were analyzed and compared in aorta tissue and the blood serum samples by reverse transcription polymerase chain reaction(RT-PCR), Western blotting, immuno-histochemistry, fluorescence resonance energy transfer ( FRET ) activity assay and enzyme-linked immuno sorbent assay ( ELISA ), respectively. Ascending aorta tissue specimens were obtained from 12 patients with an acute Stanford A-dissection at the time of aortic replacement, and from 4 patients with coronary artery disease (CAD) undergoing coronary artery bypass surgery. Meanwhile, serum samples were harvested from 15 patients with an acute Stanford A-dissection and 10 healthy individuals who served as the control group. RESULTS: MMP-12 activity could be detected in both AD and CAD groups, but the level in the AD group was higher than those in the CAD group (P < 0.05). MMP-12 proteolysis existed in both serum samples of the AD and healthy groups, and the activity level in the AD group was clearly higher than in the healthy group (P < 0.05). For AD patients, MMP-12 activity in serum was higher than in the aorta wall (P < 0.05). MMP-12 activity in the aortic wall tissue can be inhibited by MMP inhibitor v (P < 0.05). CONCLUSION: The present study directly demonstrates that MMP-12 proteolytic activity exists within the aorta specimens and blood samples from aortic dissection patients. MMP-12 might be of potential relevance as a clinically diagnostic tool and therapeutic target in vascular injury and repair.

Project description:BackgroundSarcoidosis is a chronic inflammatory disease of unknown cause characterized by granuloma formation. Mechanisms for chronic persistence of granulomas are unknown. Matrix Metalloproteinase-12 (MMP12) degrades extracellular matrix elastin and enables infiltration of immune cells responsible for inflammation and granuloma formation. Previous studies report increased MMP12 in sarcoidosis patients and association between MMP12 expression and disease severity. We also observed elevated MMP12 in our multiwall carbon nanotube (MWCNT) murine model of granulomatous inflammation. Here we hypothesized that MMP12 is important to acute and late phases of granuloma pathogenesis. To test this hypothesis, we analyzed granulomatous and inflammatory responses of Mmp12 knock-out (KO) mice at 10 (acute) and 60 days (late) after MWCNT instillation.MethodsC57BL/6 (wildtype) and Mmp12 KO mice underwent oropharyngeal instillation of MWCNT. Lungs were harvested at 3, 10, 20, and 60 days post instillation for evaluation of MMP12 expression and granulomatous changes. Bronchoalveolar lavage (BAL) cells were analyzed 60 days after MWCNT instillation for expression of mediators thought to play a role in sarcoid granulomatosis: peroxisome proliferator-activated receptor-gamma (PPARγ), interferon-gamma (IFN-γ), and CCL2 (MCP-1).ResultsPulmonary granuloma appearance at 10 days after MWCNT instillation showed no differences between wildtype and Mmp12 KO mice. In contrast, by 60 days after MWCNT instillation, Mmp12 KO mice revealed markedly attenuated granuloma formation together with elevated PPARγ and reduced IFNγ expression in BAL cells compared to wildtype. Unexpectedly, Mmp12 KO mice further demonstrated increased alveolar macrophages with increased CCL2 at 60 days.ConclusionsThe striking reduction of granuloma formation at day 60 in Mmp12 KO mice suggests that MMP12 is required to maintain chronic granuloma pathophysiology. The increased PPARγ and decreased IFNγ findings suggest that these mediators also may be involved since previous studies have shown that PPARγ suppresses IFNγ and PPARγ deficiency amplifies granuloma formation. Interestingly, a role of MMP12 in granuloma resolution is also suggested by increases in both macrophage influx and CCL2. Overall, our results strongly implicate MMP12 as a key factor in granuloma persistence and as a possible therapeutic target in chronic pulmonary sarcoidosis.

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Matrix metalloproteinase 12 overexpression in myeloid lineage cells plays a key role in modulating myelopoiesis, immune suppression, and lung tumorigenesis.

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Matrix metalloproteinase 12 overexpression in myeloid lineage cells plays a key role in modulating myelopoiesis, immune suppression, and lung tumorigenesis.

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