ETV3 and ETV6 enable monocyte differentiation into dendritic cells by repressing macrophage fate commitment

Abstract

In inflamed tissues, monocytes differentiate into macrophages (mo-Macs) or dendritic cells (mo-DCs). In chronic nonresolving inflammation, mo-DCs are major drivers of pathogenic events. Manipulating monocyte differentiation would therefore be an attractive therapeutic strategy. However, how the balance of mo-DC versus mo-Mac fate commitment is regulated is not clear. In the present study, we show that the transcriptional repressors ETV3 and ETV6 control human monocyte differentiation into mo-DCs. ETV3 and ETV6 inhibit interferon (IFN)-stimulated genes; however, their action on monocyte differentiation is independent of IFN signaling. Instead, we find that ETV3 and ETV6 directly repress mo-Mac development by controlling MAFB expression. Mice deficient for Etv6 in monocytes have spontaneous expression of IFN-stimulated genes, confirming that Etv6 regulates IFN responses in vivo. Furthermore, these mice have impaired mo-DC differentiation during inflammation and reduced pathology in an experimental autoimmune encephalomyelitis model. These findings provide information about the molecular control of monocyte fate decision and identify ETV6 as a therapeutic target to redirect monocyte differentiation in inflammatory disorders.

Monocytes differentiate along two alternative pathways during sterile inflammation

“…To dissect monocyte fate decision mechanisms, we used our previously established in vitro differentiation model, in which human monocytes are cultured with a cocktail of M‐CSF, IL4, and TNF‐α and differentiate in the same culture into mo‐DC and mo‐Mac resembling the ones found in clinical samples (Goudot et al , 2017). Of note, we have previously shown using scRNA‐seq that monocytes used in these cultures do not contain contaminating DC precursors (Villar et al , 2022). To address whether monocytes followed a binary fate decision or differentiated along a continuum of states, we sought to reconstruct monocyte differentiation trajectories using single‐cell transcriptomes.…”

“…The orphan nuclear receptor NR4A3 was also shown to participate in mo‐DC differentiation, acting downstream of IRF4, but only during inflammation in vivo (Salix et al , 2019). Similarly, ETV6 was found to control mo‐DC differentiation in vivo during inflammation but not in steady‐state (Villar et al , 2022). While the transcriptional regulation of macrophage identity in tissues is well characterized (Blériot et al , 2020; Guilliams et al , 2020), transcription factors driving the monocyte‐to‐macrophage program remain poorly characterized, besides our finding that MAFB is required for human mo‐Mac differentiation (Goudot et al , 2017).…”

“…Several molecular regulators involved in mo‐DC development have been identified using in vitro models and include IRF4, aryl hydrocarbon receptor, BLIMP‐1, NCOR2, miR‐155, ETV3, and ETV6 (Briseño et al , 2016; Goudot et al , 2017; Sander et al , 2017; Coillard et al , 2021; Mendes et al , 2021; Villar et al , 2022). The role of IRF4, aryl hydrocarbon receptor was confirmed in vivo in genetically deficient mice in homeostatic conditions (Kim et al , 2016; Goudot et al , 2017).…”

Indeterminate cell histiocytosis: A systematic review of the literature with a comprehensive revision of clinical, histopathological, and molecular features

“…ETV3 is a transcriptional repressor located at chromosome 1q23.1 that showed multiple functions in mononuclear phagocytes. Indeed, it may suppress cell growth through inhibition of the pERK pathway, repress the differentiation of monocyte to dendritic cells and inhibit interferon‐related gene transcription 133 . Moreover, ETV3 seems to be an inducible repressor of NF‐κB, and thus of inflammatory reactions 134 .…”

“…Indeed, it may suppress cell growth through inhibition of the pERK pathway, repress the differentiation of monocyte to dendritic cells and inhibit interferon-related gene transcription. 133 Moreover, ETV3 seems to be an inducible repressor of NF-κB, and thus of inflammatory reactions. 134 NCOA2 is otherwise located at chromosome 8q13.3 and encodes a transcriptional coactivator for nuclear hormone receptors that may also function as a tumour suppressor acting through inhibition of Wnt signalling.…”