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Inflammation triggers the differentiation of Ly6C^hi monocytes into microbicidal macrophages or monocyte-derived dendritic cells (moDCs). Yet, it is unclear whether environmental inflammatory cues control the polarization of monocytes toward each of these fates or whether specialized monocyte progenitor subsets exist before inflammation. Here, we have shown that naive monocytes are phenotypically heterogeneous and contain an NR4A1- and Flt3L-independent, CCR2-dependent, Flt3⁺CD11c⁻MHCII⁺PU.1^hi subset. This subset acted as a precursor for FcγRIII⁺PD-L2⁺CD209a⁺, GM-CSF-dependent moDCs but was distal from the DC lineage, as shown by fate-mapping experiments using Zbtb46. By contrast, Flt3⁻CD11c⁻MHCII⁻PU.1^lo monocytes differentiated into FcγRIII⁺PD-L2⁻CD209a⁻iNOS⁺ macrophages upon microbial stimulation. Importantly, Sfpi1 haploinsufficiency genetically distinguished the …