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Updated: Oct 16, 2025
Alveolar Macrophage Phagocytosis and Bacteria Clearance in Mice
Published on: March 2, 2019
The M2a Macrophage Phenotype Accompanies Pulmonary Granuloma Resolution in Mmp12 Knock-Out Mice Instilled with
David Ogburn1, Sophia Bhalla1, Nan Leffler1
1Division 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, USA.
Abstract:
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 Mmp12 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 Mmp12KO mice. Strikingly, an M2 macrophage phenotype was present in Mmp12KO but not in C57Bl/6 mice. Between 10 and 60 days, macrophage populations in MWCNT-instilled Mmp12KO 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 Mmp12KO mice. In conclusion, alveolar macrophages express two M2 phenotypes in Mmp12KO 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 Mmp12KO mice requires an M2a macrophage phenotype.
Insights
Matrix Metalloproteinase-12 (MMP12) deficiency resolves sarcoid-like granulomas by promoting M2 macrophage polarization. This study identifies M2a macrophages as key to granuloma resolution in MMP12-deficient mice.
Area of Science:
- Immunology
- Pulmonary Medicine
- Toxicology
Background:
- Sarcoidosis is a chronic granulomatous disease of unknown cause.
- Matrix Metalloproteinase-12 (MMP12) is implicated in active sarcoidosis granuloma persistence.
- Multiwall carbon nanotubes (MWCNT) induce sarcoid-like granulomas and MMP12 upregulation in mice.
Purpose of the Study:
- To investigate mechanisms of sarcoid-like granuloma resolution in MMP12-deficient mice.
- To identify macrophage phenotypes and molecular factors involved in granuloma resolution.
Main Methods:
- Instillation of MWCNT in wild-type and Mmp12-knockout (KO) mice.
- Analysis of macrophage populations and phenotypes (M2c, M2a) at different time points (10 and 60 days).
- Quantification of key regulatory factors, including IL-13, Apolipoprotein E (ApoE), and Matrix Metalloproteinase-14 (MMP14).
Main Results:
- Mmp12 KO mice showed initial granuloma formation followed by resolution by day 60.
- Mmp12 KO mice exhibited an M2 macrophage phenotype, shifting from M2c to M2a between days 10 and 60.
- Upregulation of IL-13, ApoE, and MMP14 was observed in resolving granulomas in Mmp12 KO mice.
Conclusions:
- MMP12 is essential for the persistence of sarcoid-like granulomas.
- Granuloma resolution in Mmp12 KO mice is associated with a shift towards an M2a macrophage phenotype.
- The M2a macrophage phenotype, potentially induced by factors like IL-13 and ApoE, plays a crucial role in sarcoidosis granuloma resolution.
