title: Transcription repressor Bach2 is required for pulmonary surfactant homeostasis and alveolar macrophage function.
abstract: Pulmonary alveolar proteinosis (PAP) results from a dysfunction of alveolar macrophages (AMs), chiefly due to disruptions in the signaling of granulocyte macrophage colony-stimulating factor (GM-CSF). We found that mice deficient for the B lymphoid transcription repressor BTB and CNC homology 2 (Bach2) developed PAP-like accumulation of surfactant proteins in the lungs. Bach2 was expressed in AMs, and Bach2-deficient AMs showed alterations in lipid handling in comparison with wild-type (WT) cells. Although Bach2-deficient AMs showed a normal expression of the genes involved in the GM-CSF signaling, they showed an altered expression of the genes involved in chemotaxis, lipid metabolism, and alternative M2 macrophage activation with increased expression of Ym1 and arginase-1, and the M2 regulator Irf4. Peritoneal Bach2-deficient macrophages showed increased Ym1 expression when stimulated with interleukin-4. More eosinophils were present in the lung and peritoneal cavity of Bach2-deficient mice compared with WT mice. The PAP-like lesions in Bach2-deficient mice were relieved by WT bone marrow transplantation even after their development, confirming the hematopoietic origin of the lesions. These results indicate that Bach2 is required for the functional maturation of AMs and pulmonary homeostasis, independently of the GM-CSF signaling.
authors.affiliation: Department of Biochemistry, 2 Division of Respiratory Medicine, and 3 Center for Regulatory Epigenome and Diseases, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nakamura
authors.forename: Risa
authors.initials: R
authors.lastname: Ebina-Shibuya
authors.forename: Ari
authors.initials: A
authors.lastname: Itoh-Nakadai
authors.forename: Akihiko
authors.initials: A
authors.lastname: Muto
authors.forename: Hiroki
authors.initials: H
authors.lastname: Shima
authors.forename: Daisuke
authors.initials: D
authors.lastname: Saigusa
authors.forename: Junken
authors.initials: J
authors.lastname: Aoki
authors.forename: Masahito
authors.initials: M
authors.lastname: Ebina
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Nukiwa
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Igarashi
mesh_terms: D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000172:deficiency / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism; D018450:Disease Progression; D004417:Dyspnea / Q000150:complications / Q000235:genetics / Q000473:pathology; D004804:Eosinophils / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006706:Homeostasis; D050835:Interferon Regulatory Factors / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics; D016676:Macrophages, Alveolar / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000378:metabolism; D051379:Mice; D010587:Phagocytosis; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D011649:Pulmonary Alveolar Proteinosis / Q000150:complications / Q000235:genetics / Q000473:pathology; D011663:Pulmonary Surfactants / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D000099232:Proto-Oncogene Protein Spi-1; D000099218:Interferon Regulatory Factor-4
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D002784:Cholesterol; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D050835:Interferon Regulatory Factors; D011518:Proto-Oncogene Proteins; D011663:Pulmonary Surfactants; D012097:Repressor Proteins; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; D000099218:Interferon Regulatory Factor-4; C102109:Bach2 protein, mouse