Transcriptional repressors as guardians of tissue macrophage identity

The association between specific transcription factors (TFs) and defined tissue-specific macrophage phenotypes is far from being univocal. Many TFs that have been associated with tissue-specific macrophages have relatively broad expression profiles suggesting the critical involvement of combinatorial regulation by multiple TFs in bringing about specific phenotypes. In the current issue of The EMBO Journal, Rauschmeier et al (2019) report the identification of the transcriptional repressors BHLHE40 and BHLHE41 as novel regulators of tissue-specific macrophage properties that work both to promote alveolar macrophage (AM) identity and to suppress alternative tissue-specific phenotypes.