Journal
NATURE IMMUNOLOGY
Volume 24, Issue 1, Pages 84-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41590-022-01374-0
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In chronic nonresolving inflammation, the differentiation of monocytes into dendritic cells plays a major role in pathogenic events. This study reveals that the transcriptional repressors ETV3 and ETV6 control this differentiation process by repressing mo-Mac development and regulating MAFB expression. Mice lacking Etv6 show spontaneous expression of IFN-stimulated genes and impaired mo-DC differentiation, suggesting ETV6 as a potential therapeutic target for redirecting monocyte differentiation in inflammatory disorders.
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.
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