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Whether these two populations derive from alternative differentiation pathways or represent different stages along a continuum remains unclear. Here, we address this question using temporal single\u2010cell RNA sequencing in an\n                    <jats:italic>in vitro<\/jats:italic>\n                    model, allowing the simultaneous differentiation of human mo\u2010Mac and mo\u2010DC. We find divergent differentiation paths, with a fate decision occurring within the first 24\u2009h and confirm this result\n                    <jats:italic>in vivo<\/jats:italic>\n                    using a mouse model of sterile peritonitis. Using a computational approach, we identify candidate transcription factors potentially involved in monocyte fate commitment. We demonstrate that IRF1 is necessary for mo\u2010Mac differentiation, independently of its role in regulating transcription of interferon\u2010stimulated genes. In addition, we describe the transcription factors ZNF366 and MAFF as regulators of mo\u2010DC development. Our results indicate that mo\u2010Macs and mo\u2010DCs represent two alternative cell fates requiring distinct transcription factors for their differentiation.\n                  <\/jats:p>","DOI":"10.15252\/embr.202256308","type":"journal-article","created":{"date-parts":[[2023,5,16]],"date-time":"2023-05-16T11:29:50Z","timestamp":1684236590000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Monocytes differentiate along two alternative pathways during sterile inflammation"],"prefix":"10.1038","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8581-4155","authenticated-orcid":false,"given":"Javiera","family":"Villar","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L\u00e9a","family":"Ouaknin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adeline","family":"Cros","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1795-1921","authenticated-orcid":false,"given":"Elodie","family":"Segura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,5,16]]},"reference":[{"key":"BFEMBR202256308_CR1","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1038\/s41590-021-01117-7","volume":"23","author":"A Amorim","year":"2022","unstructured":"Amorim A, De Feo D, Friebel E, Ingelfinger F, Anderfuhren CD, Krishnarajah S, Andreadou M, Welsh CA, Liu Z, Ginhoux F et\u00a0al (2022) IFN\u03b3 and GM\u2010CSF control complementary differentiation programs in the monocyte\u2010to\u2010phagocyte transition during neuroinflammation. 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