title: TLR Stimulation Dynamically Regulates Heme and Iron Export Gene Expression in Macrophages.
abstract: Pathogenic bacteria have evolved multiple mechanisms to capture iron or iron-containing heme from host tissues or blood. In response, organisms have developed defense mechanisms to keep iron from pathogens. Very little of the body's iron store is available as free heme; rather nearly all body iron is complexed with heme or other proteins. The feline leukemia virus, subgroup C (FeLV-C) receptor, FLVCR, exports heme from cells. It was unknown whether FLVCR regulates heme-iron availability after infection, but given that other heme regulatory proteins are upregulated in macrophages in response to bacterial infection, we hypothesized that macrophages dynamically regulate FLVCR. We stimulated murine primary macrophages or macrophage cell lines with LPS and found that Flvcr is rapidly downregulated in a TLR4/MD2-dependent manner; TLR1/2 and TLR3 stimulation also decreased Flvcr expression. We identified several candidate TLR-activated transcription factors that can bind to the Flvcr promoter. Macrophages must balance the need to sequester iron from systemic circulating or intracellular pathogens with the macrophage requirement for heme and iron to produce reactive oxygen species. Our findings underscore the complexity of this regulation and point to a new role for FLVCR and heme export in macrophages responses to infection and inflammation.
authors.affiliation: Division of Hematology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Philip
authors.affiliation: Division of Hematology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Edison Y
authors.initials: EY
authors.lastname: Chiu
authors.affiliation: Department of Comparative Medicine, University of Washington, Seattle, WA 98195, USA.
authors.forename: Adeline M
authors.initials: AM
authors.lastname: Hajjar
authors.affiliation: Division of Hematology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Janis L
authors.initials: JL
authors.lastname: Abkowitz
mesh_terms: D000818:Animals; D001052:Apoferritins / Q000235:genetics; D001692:Biological Transport; D002460:Cell Line; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D006418:Heme / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D007501:Iron / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology; D026901:Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic; D017382:Reactive Oxygen Species / Q000378:metabolism; D011991:Receptors, Virus / Q000235:genetics* / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology; D051193:Toll-Like Receptors / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: C526650:Flvcr1 protein, mouse; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D017382:Reactive Oxygen Species; D011991:Receptors, Virus; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014157:Transcription Factors; D006418:Heme; D001052:Apoferritins; D007501:Iron; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse