The Transcription Factor ZEB2 Is Required to Maintain the Tissue-Specific Identities of Macrophages

Abstract

SummaryHeterogeneity between different macrophage populations has become a defining feature of this lineage. However, the conserved factors defining macrophages remain largely unknown. The transcription factor ZEB2 is best described for its role in epithelial to mesenchymal transition; however, its role within the immune system is only now being elucidated. We show here that Zeb2 expression is a conserved feature of macrophages. Using Clec4f-cre, Itgax-cre, and Fcgr1-cre mice to target five different macrophage populations, we found that loss of ZEB2 resulted in macrophage disappearance from the tissues, coupled with their subsequent replenishment from bone-marrow precursors in open niches. Mechanistically, we found that ZEB2 functioned to maintain the tissue-specific identities of macrophages. In Kupffer cells, ZEB2 achieved this by regulating expression of the transcription factor LXRα, removal of which recapitulated the loss of Kupffer cell identity and disappearance. Thus, ZEB2 expression is required in macrophages to preserve their tissue-specific identities.

Bhlhe40 and Bhlhe41 transcription factors regulate alveolar macrophage self‐renewal and identity

“…A broad dysregulation of the AM molecular program was also reported previously for AMs deficient for the transcription factors PPARc (Schneider et al, 2014), Zeb2 (Scott et al, 2018), and Bach2 (Nakamura et al, 2013), although, in the latter case, cell-intrinsic and cell-extrinsic aspects of the changes in the expression program remain to be fully understood (Ebina-Shibuya et al, 2017). Together with this report, these studies highlight a remarkable complexity of the transcription factor network controlling the AM molecular program.…”

“…Therefore, the unique tissue‐specific identities of macrophage subsets are likely to be controlled by a combinatorial action of multiple transcription factors, some of which may be expressed more broadly than the others. In line with this notion, it was recently reported that the widely expressed transcription factor Zeb2 controls subset‐specific molecular programs in AMs, microglia, Kupffer cells, and splenic and colonic macrophages (Scott et al , ).…”

“…Of note, in many cases there is no simple one‐to‐one relationship between a macrophage subset and a transcription factor. For example, LXRα regulates marginal zone and metallophilic macrophages in the spleen and Kupffer cells in the liver (A‐Gonzalez et al , ; Scott et al , ), and PPARγ is highly expressed by both AMs and red pulp macrophages (Gautier et al , ,b). Therefore, the unique tissue‐specific identities of macrophage subsets are likely to be controlled by a combinatorial action of multiple transcription factors, some of which may be expressed more broadly than the others.…”

“…While in some cases, the loss of identity is manifested by altered expression of “canonical” cell‐surface markers, this is not always the case. For example, conditional inactivation of the pan‐macrophage transcription factor Zeb2 resulted in profound changes in expression of subset‐specific genes in AMs, microglia, Kupffer cells, and splenic and colonic macrophages, with minor effects on the expression of cell‐surface markers usually used to identify these cells (Scott et al , ). The same study also demonstrated that loss of the nuclear receptor LXRα also left a broad footprint on the Kupffer cells’ transcriptome without affecting numbers and frequency of F4/80 + CD64 + Kupffer cells in the liver.…”

Macrophages in wound healing: activation and plasticity

“…With the advent of new technologies such as single‐cell RNA‐seq (SC‐RNA Seq), a more comprehensive identification of tissue macrophage subsets has been possible. In particular, the transcription factor zinc finger E‐box binding homeobox 2 (ZEB2) was identified as a key determinant of tissue‐specific macrophages in diverse organs including the liver, lung, spleen, brain and colon . In ZEB2‐deficient mice, there was alteration of different tissue‐specific macrophage markers, highlighting the technical difficulty of identifying macrophages within tissues if using limited markers such as CD64 and F4/80.…”