title: Staphylococcus aureus recognition by hematopoietic stem and progenitor cells via TLR2/MyD88/PGE2 stimulates granulopoiesis in wounds.
abstract: 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. Lineage- 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 PGE2. Pretreatment of TLR2- or MyD88-deficient HSPCs with PGE2 rescued granulocytic differentiation in vivo. Finally, we demonstrate that bone marrow-derived lin-/Sca-1+/c-kit+ cells produced PGE2 and underwent granulopoiesis after TLR2 stimulation. lin-/Sca-1+/c-kit+ 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.
authors.affiliation: Department of Veterinary Clinical Sciences, University of Minnesota College of Veterinary Medicine, St. Paul, MN;
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Granick
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Falahee
authors.forename: Delsheen
authors.initials: D
authors.lastname: Dahmubed
authors.forename: Dori L
authors.initials: DL
authors.lastname: Borjesson
authors.forename: Lloyd S
authors.initials: LS
authors.lastname: Miller
authors.forename: Scott I
authors.initials: SI
authors.lastname: Simon
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000473:pathology; D002452:Cell Count; D002454:Cell Differentiation; D049109:Cell Proliferation; D002469:Cell Separation; D015232:Dinoprostone / Q000096:biosynthesis / Q000378:metabolism*; D005260:Female; D006098:Granulocytes / Q000276:immunology / Q000473:pathology; D006412:Hematopoietic Stem Cells / Q000276:immunology* / Q000382:microbiology; D007113:Immunity, Innate; D019891:Leukopoiesis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D012867:Skin / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D013203:Staphylococcal Infections / Q000276:immunology / Q000382:microbiology; D013211:Staphylococcus aureus / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000172:deficiency / Q000378:metabolism*; D014947:Wounds and Injuries / Q000276:immunology / Q000382:microbiology*
chemical_list: D053594:Myeloid Differentiation Factor 88; D051195:Toll-Like Receptor 2; D015232:Dinoprostone