The M2a Macrophage Phenotype Accompanies Pulmonary Granuloma Resolution in <i>Mmp12</i> Knock-Out Mice Instilled with Multiwall Carbon Nanotubes
Sarcoidosis is a chronic disease with unknown etiology and pathophysiology, characterized by granuloma formation. Matrix Metalloproteinase-12 (MMP12) is an elastase implicated in active granulomatous sarcoidosis. Previously, we reported that oropharyngeal instillation of multiwall carbon nanotubes (...
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MDPI AG
2021-10-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/20/11019 |
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| author | David Ogburn Sophia Bhalla Nan Leffler Arjun Mohan Anagha Malur Achut G. Malur Matthew McPeek Barbara P. Barna Mary Jane Thomassen |
| author_facet | David Ogburn Sophia Bhalla Nan Leffler Arjun Mohan Anagha Malur Achut G. Malur Matthew McPeek Barbara P. Barna Mary Jane Thomassen |
| author_sort | David Ogburn |
| collection | DOAJ |
| description | Sarcoidosis is a chronic disease with unknown etiology and pathophysiology, characterized by granuloma formation. Matrix Metalloproteinase-12 (MMP12) is an elastase implicated in active granulomatous sarcoidosis. Previously, we reported that oropharyngeal instillation of multiwall carbon nanotubes (MWCNT) into C57Bl/6 mice induced sarcoid-like granulomas and upregulation of MMP12. When <i>Mmp12</i> knock-out (KO) mice were instilled with MWCNT, granuloma formation occurred 10 days post-instillation but subsequently resolved at 60 days. Thus, we concluded that MMP12 was essential to granuloma persistence. The aim of the current study was to identify potential mechanisms of granuloma resolution in <i>Mmp12</i>KO mice. Strikingly, an M2 macrophage phenotype was present in <i>Mmp12</i>KO but not in C57Bl/6 mice. Between 10 and 60 days, macrophage populations in MWCNT-instilled <i>Mmp12</i>KO mice demonstrated an M2c to M2a phenotypic shift, with elevations in levels of IL-13, an M2 subtype-regulating factor. Furthermore, the M2 inducer, Apolipoprotein E (ApoE), and Matrix Metalloproteinase-14 (MMP14), a promoter of collagen degradation, were upregulated in 60-day MWCNT-instilled <i>Mmp12</i>KO mice. In conclusion, alveolar macrophages express two M2 phenotypes in <i>Mmp12</i>KO mice: M2c at 10 days when granulomas form, and M2a at 60 days when granulomas are resolving. Findings suggest that granuloma resolution in 60-day <i>Mmp12</i>KO mice requires an M2a macrophage phenotype. |
| first_indexed | 2024-03-10T06:30:36Z |
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| language | English |
| last_indexed | 2024-03-10T06:30:36Z |
| publishDate | 2021-10-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-3ab26768b0314c9dbbb18eb195bbb15b2023-11-22T18:32:30ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-10-0122201101910.3390/ijms222011019The M2a Macrophage Phenotype Accompanies Pulmonary Granuloma Resolution in <i>Mmp12</i> Knock-Out Mice Instilled with Multiwall Carbon NanotubesDavid Ogburn0Sophia Bhalla1Nan Leffler2Arjun Mohan3Anagha Malur4Achut G. Malur5Matthew McPeek6Barbara P. Barna7Mary Jane Thomassen8Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Brody School of Medicine Sciences Building, East Carolina University, Moye Boulevard, Greenville, NC 27834, USADivision of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Brody School of Medicine Sciences Building, East Carolina University, Moye Boulevard, Greenville, NC 27834, USADivision of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Brody School of Medicine Sciences Building, East Carolina University, Moye Boulevard, Greenville, NC 27834, USADivision of Pulmonary Disease and Critical Care Medicine, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23284, USADivision of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Brody School of Medicine Sciences Building, East Carolina University, Moye Boulevard, Greenville, NC 27834, USADepartment of Microbiology & Immunology, St. George’s University, St. George 999166, GrenadaDivision of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Brody School of Medicine Sciences Building, East Carolina University, Moye Boulevard, Greenville, NC 27834, USADivision of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Brody School of Medicine Sciences Building, East Carolina University, Moye Boulevard, Greenville, NC 27834, USADivision of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Brody School of Medicine Sciences Building, East Carolina University, Moye Boulevard, Greenville, NC 27834, USASarcoidosis is a chronic disease with unknown etiology and pathophysiology, characterized by granuloma formation. Matrix Metalloproteinase-12 (MMP12) is an elastase implicated in active granulomatous sarcoidosis. Previously, we reported that oropharyngeal instillation of multiwall carbon nanotubes (MWCNT) into C57Bl/6 mice induced sarcoid-like granulomas and upregulation of MMP12. When <i>Mmp12</i> knock-out (KO) mice were instilled with MWCNT, granuloma formation occurred 10 days post-instillation but subsequently resolved at 60 days. Thus, we concluded that MMP12 was essential to granuloma persistence. The aim of the current study was to identify potential mechanisms of granuloma resolution in <i>Mmp12</i>KO mice. Strikingly, an M2 macrophage phenotype was present in <i>Mmp12</i>KO but not in C57Bl/6 mice. Between 10 and 60 days, macrophage populations in MWCNT-instilled <i>Mmp12</i>KO mice demonstrated an M2c to M2a phenotypic shift, with elevations in levels of IL-13, an M2 subtype-regulating factor. Furthermore, the M2 inducer, Apolipoprotein E (ApoE), and Matrix Metalloproteinase-14 (MMP14), a promoter of collagen degradation, were upregulated in 60-day MWCNT-instilled <i>Mmp12</i>KO mice. In conclusion, alveolar macrophages express two M2 phenotypes in <i>Mmp12</i>KO mice: M2c at 10 days when granulomas form, and M2a at 60 days when granulomas are resolving. Findings suggest that granuloma resolution in 60-day <i>Mmp12</i>KO mice requires an M2a macrophage phenotype.https://www.mdpi.com/1422-0067/22/20/11019sarcoidosisMMP12PPARγMWCNTgranulomainflammation |
| spellingShingle | David Ogburn Sophia Bhalla Nan Leffler Arjun Mohan Anagha Malur Achut G. Malur Matthew McPeek Barbara P. Barna Mary Jane Thomassen The M2a Macrophage Phenotype Accompanies Pulmonary Granuloma Resolution in <i>Mmp12</i> Knock-Out Mice Instilled with Multiwall Carbon Nanotubes International Journal of Molecular Sciences sarcoidosis MMP12 PPARγ MWCNT granuloma inflammation |
| title | The M2a Macrophage Phenotype Accompanies Pulmonary Granuloma Resolution in <i>Mmp12</i> Knock-Out Mice Instilled with Multiwall Carbon Nanotubes |
| title_full | The M2a Macrophage Phenotype Accompanies Pulmonary Granuloma Resolution in <i>Mmp12</i> Knock-Out Mice Instilled with Multiwall Carbon Nanotubes |
| title_fullStr | The M2a Macrophage Phenotype Accompanies Pulmonary Granuloma Resolution in <i>Mmp12</i> Knock-Out Mice Instilled with Multiwall Carbon Nanotubes |
| title_full_unstemmed | The M2a Macrophage Phenotype Accompanies Pulmonary Granuloma Resolution in <i>Mmp12</i> Knock-Out Mice Instilled with Multiwall Carbon Nanotubes |
| title_short | The M2a Macrophage Phenotype Accompanies Pulmonary Granuloma Resolution in <i>Mmp12</i> Knock-Out Mice Instilled with Multiwall Carbon Nanotubes |
| title_sort | m2a macrophage phenotype accompanies pulmonary granuloma resolution in i mmp12 i knock out mice instilled with multiwall carbon nanotubes |
| topic | sarcoidosis MMP12 PPARγ MWCNT granuloma inflammation |
| url | https://www.mdpi.com/1422-0067/22/20/11019 |
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