Staphylococcus aureus recognition by hematopoietic stem and progenitor cells via TLR2/MyD88/PGE₂ stimulates granulopoiesis in wounds

During bacterial infection, hematopoietic stem and progenitor cells (HSPCs) differentiate into polymorphonuclear leukocytes (PMNs) in the bone marrow. We reported that HSPCs recruited to Staphylococcus aureus–infected skin wounds in mice undergo granulopoiesis, whereas other authors have demonstrated their differentiation in vitro after Toll-like receptor 2 (TLR2)/MyD88 stimulation. Here, we examined this pathway in HSPC trafficking and granulopoiesis within S aureus–infected wounds. Lineage² HSPCs from TLR2- or MyD88-deficient mice injected into infected wounds of wild-type (WT) mice exhibited impaired granulopoiesis. However, HSPCs from WT mice produced similar numbers of PMNs whether transferred into wounds of TLR2-, MyD88-deficient, or WT mice. Prostaglandin E₂ (PGE₂), which stimulates HSPC survival and proliferation, was produced by HSPCs after TLR2 stimulation, suggesting that TLR2/MyD88 activation promotes granulopoiesis in part by production and autocrine activity of PGE_2. Pretreatment of TLR2- or MyD88-deficient HSPCs with PGE₂ rescued granulocytic differentiation in vivo. Finally, we demonstrate that bone marrow–derived lin²/Sca-1¹/c-kit¹ cells produced PGE₂ and underwent granulopoiesis after TLR2 stimulation. lin²/Sca-1¹/c-kit¹ cells deficient in TLR2 or MyD88 produced PMNs after PGE₂ treatment when transferred into uninfected wounds. We conclude that granulopoiesis in S aureus–infected wounds is induced by TLR2/MyD88 activation of HSPCs through a mechanism that involves autocrine production and activity of PGE₂.