ICAM-1 and vascular matrices coordinate skin S1 macrophage formation from blood PDGFRα lineage monocyte

Extravasation control of leukocytes and their functional fates are crucial to maintain tissue homeostasis. Leukocyte lineage origin regulates these processes that blood monocytes derived from PDGFRα+ embryonic progenitors (PDGFRα lineage) extravasate more efficiently to inflamed skin than non-PDGFRα lineage cells. Here, we elucidated the underlying mechanism and their macrophage identity fates in skin. Spatial confocal imaging showed PDGFRα lineage monocytes adhered better on venular endothelium than non-PDGFRα lineage before transvenular migration dependently on ICAM-1. At endothelial interface, more ICAM-1 aggregates were observed with PDGFRα lineage monocytes and disruption with a Src-family kinases antagonist reduced adhesion advantage. Extravasated PDGFRα lineage monocytes exhibited slower β1-integrin-dependent migration to interstitium and remained proximal to hypodermal capillaries. Skin-interstitial fibronectin binds integrin-α5 and activates Src-family kinases to suppress macrophage expression of S1-marking CD163. By accessing nearby vascular matrices, PDGFRα lineage monocytes mitigated this effect and developed stronger S1 identity. Together, extravasation fate of PDGFRα lineage monocyte/macrophage reveals the vasculatures foster S1 macrophage identity formation in skin.