Inhibition of Elastase-Pulmonary Emphysema in Dominant-Negative MafB Transgenic Mice

Abstract

Alveolar macrophages (AMs) play important roles in the pathogenesis of chronic obstructive pulmonary disease (COPD). We previously demonstrated upregulation of the transcription factor MafB in AMs of mice exposed to cigarette smoke. The aim of this study was to elucidate the roles of MafB in the development of pulmonary emphysema. Porcine pancreatic elastase was administered to wild-type (WT) and dominant-negative (DN)-MafB transgenic (Tg) mice in which MafB activity was suppressed only in macrophages. We measured the mean linear intercept and conducted cell differential analysis of bronchoalveolar lavage (BAL) cells, surface marker analysis using flow cytometry, and immunohistochemical staining using antibodies to matrix metalloproteinase (MMP)-9 and MMP-12. Airspace enlargement of the lungs was suppressed significantly in elastase-treated DN-MafB Tg mice compared with treated WT mice. AMs with projected pseudopods were decreased in DN-MafB Tg mice. The number of cells intermediately positive for F4/80 and weakly or intermediately positive for CD11b, which are considered cell subsets of matured AMs, decreased in the BAL of DN-MafB Tg mice. Furthermore, MMP-9 and -12 were significantly downregulated in BAL cells of DN-MafB Tg mice. Because MMPs exacerbate emphysema, MafB may be involved in pulmonary emphysema development through altered maturation of macrophages and MMP expression.

MAFB Determines Human Macrophage Anti-Inflammatory Polarization: Relevance for the Pathogenic Mechanisms Operating in Multicentric Carpotarsal Osteolysis

“…However, we have observed that MCTO mutations limit the acquisition of GM-CSF-inducible genes in GM-MØ, a finding that might be relevant in the case of macrophages whose development is critically dependent on GM-CSF (lung alveolar macrophages) (69). Although no lung-associated pathology has been to date reported in MCTO patients, it is worth noting that a significant number of genes aberrantly expressed in pulmonary diseases (pulmonary sarcoidosis, asthma, and tuberculosis) exhibit an altered expression in MCTO M-MØ, a finding that might be related to the fact that mature alveolar macrophages, identified as intermediate positive for the Emr1-encoded F4/80, are reduced in the bronchoalveolar lavage of mice expressing a dominant-negative MafB in macrophages (70). Given these antecedents, the analysis of further MCTO patients, it is certainly worthy as a means to get a deeper knowledge of the molecular mechanisms operating in this and other related osteolytic syndromes as well as to more clearly delineate the role of MAFB in the acquisition of the human macrophage anti-inflammatory profile.…”

Role of inflammatory cells in airway remodeling in COPD

“… 18 In animal models of COPD, it demonstrated that dominant-negative MafB suppressed porcine pancreatic elastase-induced emphysema by downregulating MMPs. 19 Considering the significant role of MMP-9 in the above studies, it may be worthwhile exploring its role in the function of different primary cells from patients with disease.…”

The role of macrophage transcription factor MafB in atherosclerotic plaque stability

“…Since MafB knockout mice die after birth due to developmental anomalies of neurons in the respiratory center [9], we generated transgenic mice with macrophage-specific dominant negative (DN)-MafB by using the macrophage scavenger receptor (MSR) enhancerpromoter [10,11]. A truncated form of MafB lacking an N-terminal acidic domain reportedly acts in a dominant negative manner [4].…”