Tissue Inhibitor of Metalloproteinases–3 Moderates the Proinflammatory Status of Macrophages
| Autor: | Samuel W. Sussman, Anne M. Manicone, William C. Parks, Cliff Rims, Sina A. Gharib, Ying Wang, John K. McGuire, Sean E. Gill, Roy T. Wang, Eli M. Bench, Timothy P. Birkland |
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| Rok vydání: | 2013 |
| Předmět: |
Pulmonary and Respiratory Medicine
Time Factors Genotype Cellular differentiation Clinical Biochemistry Macrophage polarization Inflammation Lung injury Biology CCL2 Proinflammatory cytokine Mice medicine Animals Macrophage Molecular Biology Mice Knockout Tissue Inhibitor of Metalloproteinase-3 Macrophages Cell Differentiation Articles Pneumonia Cell Biology Molecular biology Mice Inbred C57BL Disease Models Animal Phenotype Gene Expression Regulation Neutrophil Infiltration Interleukin 12 Cytokines Inflammation Mediators medicine.symptom |
| Zdroj: | American Journal of Respiratory Cell and Molecular Biology. 49:768-777 |
| ISSN: | 1535-4989 1044-1549 |
| DOI: | 10.1165/rcmb.2012-0377oc |
| Popis: | Tissue inhibitor of metalloproteinases-3 (TIMP-3) has emerged as a key mediator of inflammation. Recently, we reported that the resolution of inflammation is impaired in Timp3(-/-) mice after bleomycin-induced lung injury. Here, we demonstrate that after LPS instillation (another model of acute lung injury), Timp3(-/-) mice demonstrate enhanced and persistent neutrophilia, increased numbers of infiltrated macrophages, and delayed weight gain, compared with wild-type (WT) mice. Because macrophages possess broad immune functions and can differentiate into cells that either stimulate inflammation (M1 macrophages) or are immunosuppressive (M2 macrophages), we examined whether TIMP-3 influences macrophage polarization. Comparisons of the global gene expression of unstimulated or LPS-stimulated bone marrow-derived macrophages (BMDMs) from WT and Timp3(-/-) mice revealed that Timp3(-/-) BMDMs exhibited an increased expression of genes associated with proinflammatory (M1) macrophages, including Il6, Il12, Nos2, and Ccl2. Microarray analyses also revealed a baseline difference in gene expression between WT and Timp3(-/-) BMDMs, suggesting altered macrophage differentiation. Furthermore, the treatment of Timp3(-/-) BMDMs with recombinant TIMP-3 rescued this altered gene expression. We also examined macrophage function, and found that Timp3(-/-) M1 cells exhibit significantly more neutrophil chemotactic activity and significantly less soluble Fas ligand-induced caspase-3/7 activity, a marker of apoptosis, compared with WT M1 cells. Macrophage differentiation into immunosuppressive M2 cells is mediated by exposure to IL-4/IL-13, and we found that Timp3(-/-) M2 macrophages demonstrated a lower expression of genes associated with an anti-inflammatory phenotype, compared with WT M2 cells. Collectively, these findings indicate that TIMP-3 functions to moderate the differentiation of macrophages into proinflammatory (M1) cells. |
| Databáze: | OpenAIRE |
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