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Immunol."],"abstract":"<jats:p>Upon migrating into the tissues, hematopoietic stem cell (HSC)-derived monocytes differentiate into macrophages, playing a crucial role in determining innate immune responses towards external pathogens and internal stimuli. However, the regulatory mechanisms underlying monocyte-to-macrophage differentiation remain largely unexplored. Here we divulge a previously uncharacterized but essential role for an axon guidance molecule, fibronectin leucine-rich transmembrane protein 2 (FLRT2), in monocyte-to-macrophage maturation. FLRT2 is almost undetectable in human monocytic cell lines, human peripheral blood mononuclear cells (PBMCs), and mouse primary monocytes but significantly increases in fully differentiated macrophages. Myeloid-specific deletion of FLRT2 (<jats:italic>Flrt2<jats:sup>\u0394Myel<\/jats:sup><\/jats:italic>) contributes to decreased peritoneal monocyte-to-macrophage generation in mice <jats:italic>in vivo<\/jats:italic>, accompanied by impaired macrophage functions. Gain- and loss-of-function studies support the promoting effect of FLRT2 on THP-1 cell and human PBMC differentiation into macrophages. Mechanistically, FLRT2 directly interacts with Unc-5 netrin receptor B (UNC5B) <jats:italic>via<\/jats:italic> its extracellular domain (ECD) and activates Akt\/mTOR signaling. <jats:italic>In vivo<\/jats:italic> administration of mTOR agonist MYH1485 reverses the impaired phenotypes observed in <jats:italic>Flrt2<jats:sup>\u0394Myel<\/jats:sup><\/jats:italic> mice. Together, these results identify FLRT2 as a novel pivotal endogenous regulator of monocyte differentiation into macrophages. Targeting the FLRT2\/UNC5B-Akt\/mTOR axis may provide potential therapeutic strategies directly relevant to human diseases associated with aberrant monocyte\/macrophage differentiation.<\/jats:p>","DOI":"10.3389\/fimmu.2023.1162004","type":"journal-article","created":{"date-parts":[[2023,4,6]],"date-time":"2023-04-06T04:32:14Z","timestamp":1680755534000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":14,"title":["Fibronectin leucine-rich transmembrane protein 2 drives monocyte differentiation into macrophages via the UNC5B-Akt\/mTOR 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