title: Aspergillus fumigatus antigens activate innate immune cells via toll-like receptors 2 and 4.
abstract: Invasive aspergillosis (IA) is a leading cause of mortality in haematological patients. Appropriate activation of the innate immune system is crucial for the successful clearance of IA. Therefore, we studied the Aspergillus fumigatus-mediated activation of human granulocytes and monocyte-derived immature dendritic cells (DCs), as well as murine bone marrow-derived DCs (BMDCs) from wild type, toll-like receptor (TLR)4-deficient, TLR2 knockout, and TLR2/TLR4 double deficient mice. Aspergillus fumigatus antigens induced the activation and maturation of immature DCs as characterized by CD83 expression, upregulation of major histocompatibility complex and co-stimulatory molecules. Moreover, fungal antigens enhanced the phagocytosis and production of interleukin (IL)-8 in granulocytes. The release of IL-12 by BMDCs in response to A. fumigatus antigens was dependent on the expression of TLR2, whereas the release of IL-6 was dependent on the expression of functional TLR4 molecules. The protein precipitate of A. fumigatus supernatant provided strong stimulation of DCs and granulocytes, indicating that a factor secreted by A. fumigatus might activate innate immune cells. In conclusion, A. fumigatus antigens induced the activation of DCs and granulocytes. Our results indicated that this activation was mediated via TLR2 and TLR4. Future studies are needed to assess the clinical impact of these findings in patients at high risk for IA.
authors.affiliation: Institute for Cell Biology, Eberhard-Karls-Universität Tuuml;bingen, Tübingen, Germany.
authors.forename: Sibylla
authors.initials: S
authors.lastname: Braedel
authors.forename: Markus
authors.initials: M
authors.lastname: Radsak
authors.forename: Hermann
authors.initials: H
authors.lastname: Einsele
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Latgé
authors.forename: Andreas
authors.initials: A
authors.lastname: Michan
authors.forename: Juergen
authors.initials: J
authors.lastname: Loeffler
authors.forename: Ziad
authors.initials: Z
authors.lastname: Haddad
authors.forename: Ulrich
authors.initials: U
authors.lastname: Grigoleit
authors.forename: Hansjoerg
authors.initials: H
authors.lastname: Schild
authors.forename: Holger
authors.initials: H
authors.lastname: Hebart
mesh_terms: D000818:Animals; D000946:Antigens, Fungal / Q000276:immunology*; D001232:Aspergillus fumigatus / Q000276:immunology*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology; D006801:Humans; D007111:Immunity, Cellular; D007378:Interleukins / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D018375:Neutrophil Activation / Q000276:immunology; D009504:Neutrophils / Q000276:immunology; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology*; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
chemical_list: D000946:Antigens, Fungal; D007378:Interleukins; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors