Inflammatory responses induce an identity crisis of alveolar macrophages, leading to pulmonary alveolar proteinosis

• Published in: The Journal of biological chemistry 2017-11, Vol.292 (44), p.18098-18112
• Main Authors: Ebina-Shibuya, Risa, Matsumoto, Mitsuyo, Kuwahara, Makoto, Jang, Kyoung-Jin, Sugai, Manabu, Ito, Yoshiaki, Funayama, Ryo, Nakayama, Keiko, Sato, Yuki, Ishii, Naoto, Okamura, Yasunobu, Kinoshita, Kengo, Kometani, Kohei, Kurosaki, Tomohiro, Muto, Akihiko, Ichinose, Masakazu, Yamashita, Masakatsu, Igarashi, Kazuhiko
• Format: Article
• Language: English
• Subjects: Animals; Basic-Leucine Zipper Transcription Factors - genetics; Basic-Leucine Zipper Transcription Factors - metabolism; Biomarkers - metabolism; Cell Lineage; Cells, Cultured; Chromatin Immunoprecipitation; Dendritic Cells - immunology; Dendritic Cells - metabolism; Dendritic Cells - pathology; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Gene Expression Profiling; Gene Expression Regulation; Heterozygote; Immunity, Innate; Immunology; inflammation; Lung - immunology; Lung - metabolism; Lung - pathology; Lymphocyte Activation; Lymphocyte Depletion; macrophage; Macrophages, Alveolar - immunology; Macrophages, Alveolar - metabolism; Macrophages, Alveolar - pathology; Mice; Mice, Knockout; Mice, Transgenic; Pulmonary Alveolar Proteinosis - immunology; Pulmonary Alveolar Proteinosis - metabolism; Pulmonary Alveolar Proteinosis - pathology; pulmonary surfactant; Specific Pathogen-Free Organisms; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; T-Lymphocytes - pathology; transcription factor
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M117.808535

Pulmonary alveolar proteinosis (PAP) is a severe respiratory disease characterized by dyspnea caused by accumulation of surfactant protein. Dysfunction of alveolar macrophages (AMs), which regulate the homeostasis of surfactant protein, leads to the development of PAP; for example, in mice lacking BTB and CNC homology 2 (Bach2). However, how Bach2 helps prevent PAP is unknown, and the cell-specific effects of Bach2 are undefined. Using mice lacking Bach2 in specific cell types, we found that the PAP phenotype of Bach2-deficient mice is due to Bach2 deficiency in more than two types of immune cells. Depletion of hyperactivated T cells in Bach2-deficient mice restored normal function of AMs and ameliorated PAP. We also found that, in Bach2-deficient mice, hyperactivated T cells induced gene expression patterns that are specific to other tissue-resident macrophages and dendritic cells. Moreover, Bach2-deficient AMs exhibited a reduction in cell cycle progression. IFN-γ released from T cells induced Bach2 expression in AMs, in which Bach2 then bound to regulatory regions of inflammation-associated genes in myeloid cells. Of note, in AMs, Bach2 restricted aberrant responses to excessive T cell-induced inflammation, whereas, in T cells, Bach2 puts a brake on T cell activation. Moreover, Bach2 stimulated the expression of multiple histone genes in AMs, suggesting a role of Bach2 in proper histone expression. We conclude that Bach2 is critical for the maintenance of AM identity and self-renewal in inflammatory environments. Treatments targeting T cells may offer new therapeutic strategies for managing secondary PAP.