Experimental Pneumocystis lung infection promotes M2a alveolar macrophage-derived MMP12 production.

Abstract

Among several bacterial and viral pathogens, the atypical fungal organism Pneumocystis jirovecii has been implicated as a contributor to the pathogenesis of chronic obstructive pulmonary disease (COPD). In a previous study, we reported that Pneumocystis-colonized HIV-positive subjects had worse obstruction of airways and higher sputum levels of macrophage elastase/matrix metalloproteinase 12 (MMP12), a protease strongly associated with the development of COPD. Here, we examined parameters of Pneumocystis-induced MMP12 in the lungs of mice and its role in the lung immune response to murine Pneumocystis. Initial studies demonstrated that P. murina exposure induced Mmp12 mRNA expression in whole lungs and alveolar macrophages (AMs), which was dependent on the presence of CD4+ T cells as well as signal transducer and activator of transcription 6. Mmp12 mRNA expression was upregulated in AMs by interleukin (IL)-4 treatment, but downregulated by interferon (IFN)-γ, indicating preferential expression in alternatively activated (M2a) macrophages. IL-4 treatment induced the 54-kDa proenzyme form of MMP12 and the 22-kDa fully processed and active form, whereas IFN-γ failed to induce either. Despite a reported antimicrobial role in macrophage phagolysosomes, mice deficient in MMP12 were not found to be more susceptible to lung infection with P. murina. Collectively, our data indicate that MMP12 induction is a component of the P. murina-induced M2 response and thus provides insight into the link between Pneumocystis colonization/infection and exacerbations in COPD.

• Authors: Michael P Nelson, Benjamin S Christmann, Chad W Dunaway, Alison Morris, Chad Steele
• Journal: American journal of physiology. Lung cellular and molecular physiology (Am J Physiol Lung Cell Mol Physiol) Vol. 303 Issue 5 Pg. L469-75 (Sep 2012) ISSN: 1522-1504 [Electronic] United States
• PMID: 22773692 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• STAT4 Transcription Factor
• STAT6 Transcription Factor
• Stat4 protein, mouse
• Stat6 protein, mouse
• src-Family Kinases
• Matrix Metalloproteinase 12

Topics

• Animals
• CD4-Positive T-Lymphocytes (immunology)
• Cells, Cultured
• Gene Expression
• Immunity, Innate
• Lymphocyte Depletion
• Macrophages (enzymology)
• Male
• Matrix Metalloproteinase 12 (genetics, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Pneumocystis
• Pneumonia, Pneumocystis (enzymology, immunology, pathology)
• Pulmonary Alveoli (immunology, pathology)
• STAT4 Transcription Factor (metabolism)
• STAT6 Transcription Factor (metabolism)
• src-Family Kinases (deficiency)