期刊
EMBO JOURNAL
卷 38, 期 19, 页码 -出版社
WILEY
DOI: 10.15252/embj.2018101233
关键词
alveolar macrophages; Bhlhe40; Bhlhe41; self-renewal; tissue-resident macrophages
资金
- Boehringer Ingelheim
- Austrian Science Fund [P28841]
- Austrian Industrial Research Promotion Agency [FFG-852936]
- Swedish Research Council [2017-01118]
- Cancerfonden [CAN 2018/710]
- Angstromke Wibergs Stiftelse [M18-0094]
- Agence Nationale de la Recherche [ANR-11-BSV3-0026]
- Fondation pour la Recherche Medicale [DEQ.20110421320]
- European Research Council (ERC) under the European Union [695093 MacAge]
- German Research Foundation DFG [RE 4264/1-1]
- Formas [2017-01118] Funding Source: Formas
- Swedish Research Council [2017-01118] Funding Source: Swedish Research Council
- Austrian Science Fund (FWF) [P28841] Funding Source: Austrian Science Fund (FWF)
- Agence Nationale de la Recherche (ANR) [ANR-11-BSV3-0026] Funding Source: Agence Nationale de la Recherche (ANR)
Tissues in multicellular organisms are populated by resident macrophages, which perform both generic and tissue-specific functions. The latter are induced by signals from the microenvironment and rely on unique tissue-specific molecular programs requiring the combinatorial action of tissue-specific and broadly expressed transcriptional regulators. Here, we identify the transcription factors Bhlhe40 and Bhlhe41 as novel regulators of alveolar macrophages (AMs)-a population that provides the first line of immune defense and executes homeostatic functions in lung alveoli. In the absence of these factors, AMs exhibited decreased proliferation that resulted in a severe disadvantage of knockout AMs in a competitive setting. Gene expression analyses revealed a broad cell-intrinsic footprint of Bhlhe40/Bhlhe41 deficiency manifested by a downregulation of AM signature genes and induction of signature genes of other macrophage lineages. Genome-wide characterization of Bhlhe40 DNA binding suggested that these transcription factors directly repress the expression of lineage-inappropriate genes in AMs. Taken together, these results identify Bhlhe40 and Bhlhe41 as key regulators of AM self-renewal and guardians of their identity.
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