PDGFRα‐lineage origin directs monocytes to trafficking proficiency to support peripheral immunity

Multiple embryonic precursors give rise to leukocytes in adults while the lineage‐based functional impacts are underappreciated. Mesodermal precursors expressing PDGFRα appear transiently during E7.5‐8.5 descend to a subset of Lin–Sca1+Kit+ hematopoietic progenitors found in adult BM. By analyzing a PDGFRα‐lineage tracing mouse line, we here report that PDGFRα‐lineage BM F4/80+SSClo monocytes/macrophages are solely Ly6C+LFA‐1hiMac‐1hi monocytes enriched on the abluminal sinusoidal endothelium while Ly6C–LFA‐1loMac‐1lo macrophages are mostly from non‐PDGFRα‐lineage in vivo. Monocytes with stronger integrin profiles outcompete macrophages for adhesion on an endothelial monolayer or surfaces coated with ICAM‐1‐Fc or VCAM‐1‐Fc. Egress of PDGFRα‐lineage‐rich monocytes and subsequent differentiation to peripheral macrophages spatially segregates them from non‐PDGFRα‐lineage BM‐resident macrophages and allows functional specialization since macrophages derived from these egressing monocytes differ in morphology, phenotype, and functionality from BM‐resident macrophages in culture. Extravasation preference for blood PDGFRα‐lineage monocytes varies by tissues and governs the local lineage composition of macrophages. More PDGFRα‐lineage classical monocytes infiltrated into skin and colon but not into peritoneum. Accordingly, transcriptomic analytics indicated augmented inflammatory cascades in dermatitis skin of BM‐chimeric mice harbouring only PDGFRα‐lineage leukocytes. Thus, the PDGFRα‐lineage origin biasedly generates monocytes predestined for BM exit to support peripheral immunity following extravasation and macrophage differentiation. After differentiation from hematopoietic progenitors, monocytes either intravasate to circulation or differentiate to macrophages in BM. BM‐resident macrophages are solely derived from non‐PDGFRα‐lineage while both lineages supply trafficking monocytes to circulation as LFA‐1hiMac‐1hiCD115+Ly6C+ cells. Extravasation preference for PDGFRα‐lineage classical monocytes varies by tissues and might affect macrophage functions after differentiation.