title: TLRs govern neutrophil activity in aspergillosis.
abstract: Polymorphonuclear neutrophils (PMNs) are essential in initiation and execution of the acute inflammatory response and subsequent resolution of fungal infection. PMNs, however, may act as double-edged swords, as the excessive release of oxidants and proteases may be responsible for injury to organs and fungal sepsis. To identify regulatory mechanisms that may balance PMN-dependent protection and immunopathology in fungal infections, the involvement of different TLR-activation pathways was evaluated on human PMNs exposed to the fungus Aspergillus fumigatus. Recognition of Aspergillus and activation of PMNs occurred through the involvement of distinct members of the TLR family, each likely activating specialized antifungal effector functions. By affecting the balance between fungicidal oxidative and nonoxidative mechanisms, pro- and anti-inflammatory cytokine production, and apoptosis vs necrosis, the different TLRs ultimately impacted on the quality of microbicidal activity and inflammatory pathology. Signaling through TLR2 promoted the fungicidal activity of PMNs through oxidative pathways involving extracellular release of gelatinases and proinflammatory cytokines while TLR4 favored the oxidative pathways through the participation of azurophil, myeloperoxidase-positive, granules and IL-10. This translated in vivo in the occurrence of different patterns of fungal clearance and inflammatory pathology. Both pathways were variably affected by signaling through TLR3, TLR5, TLR6, TLR7, TLR8, and TLR9. The ability of selected individual TLRs to restore antifungal functions in defective PMNs suggests that the coordinated outputs of activation of multiple TLRs may contribute to PMN function in aspergillosis.
authors.affiliation: Microbiology Section, Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Bellocchio
authors.forename: Silvia
authors.initials: S
authors.lastname: Moretti
authors.forename: Katia
authors.initials: K
authors.lastname: Perruccio
authors.forename: Francesca
authors.initials: F
authors.lastname: Fallarino
authors.forename: Silvia
authors.initials: S
authors.lastname: Bozza
authors.forename: Claudia
authors.initials: C
authors.lastname: Montagnoli
authors.forename: Paolo
authors.initials: P
authors.lastname: Mosci
authors.forename: Grayson B
authors.initials: GB
authors.lastname: Lipford
authors.forename: Lucia
authors.initials: L
authors.lastname: Pitzurra
authors.forename: Luigina
authors.initials: L
authors.lastname: Romani
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D001228:Aspergillosis / Q000276:immunology* / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D001232:Aspergillus fumigatus / Q000254:growth & development / Q000276:immunology; D015550:Cell Degranulation / Q000276:immunology; D002460:Cell Line; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D006801:Humans; D025301:Hyphae / Q000276:immunology; D008562:Membrane Glycoproteins / Q000819:agonists / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009336:Necrosis / Q000276:immunology; D018375:Neutrophil Activation / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology; D016877:Oxidants / Q000096:biosynthesis; D010587:Phagocytosis / Q000276:immunology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000819:agonists / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology*; D013172:Spores, Fungal / Q000276:immunology; D051195:Toll-Like Receptor 2; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051198:Toll-Like Receptor 5; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors
chemical_list: D016207:Cytokines; D008562:Membrane Glycoproteins; D016877:Oxidants; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; C495342:TLR2 protein, human; C495344:TLR3 protein, human; C495345:TLR4 protein, human; C495346:TLR5 protein, human; C495348:TLR7 protein, human; C495349:TLR8 protein, human; C495371:TLR9 protein, human; D051195:Toll-Like Receptor 2; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051198:Toll-Like Receptor 5; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors