title: PTX3 binds MD-2 and promotes TRIF-dependent immune protection in aspergillosis.
abstract: The long pentraxin 3 (PTX3) modulates different effector pathways involved in innate resistance to Aspergillus fumigatus, including complement activation or promotion of phagocytosis by interacting with FcγRs. However, whether and how TLRs modulate PTX3 mediates antifungal resistance is not known. In this study, we demonstrate that PTX3 binds myeloid differentiation protein 2 (MD-2) in vitro and exerts its protective antifungal activity in vivo through TLR4/MD-2-mediated signaling. Similar to Tlr4(-/-) mice, Md2(-/-) mice displayed high susceptibility to pulmonary aspergillosis, a phenotype associated with a proinflammatory cytokine profile and impaired antifungal activity of polymorphonuclear neutrophils. Treating Md2(-/-) mice with PTX3 failed to confer immune protection against the fungus, whereas adoptive transfer of MD-2-competent polymorphonuclear neutrophils restored it. Mechanistically, engagement of MD-2 by PTX3-opsonized Aspergillus conidia activated the TLR4/Toll/IL-1R domain-containing adapter inducing IFN-β-dependent signaling pathway converging on IL-10. Thus, we have identified a novel receptor mechanism, involving the TLR4/MD-2/Toll/IL-1R domain-containing adapter inducing IFN-β-mediated signaling, whereby PTX3 elicits antifungal resistance with limited immunopathology in A. fumigatus infection.
authors: Department of Experimental Medicine, University of Perugia, Perugia 06132, Italy;
authors: Silvia
authors: S
authors: Bozza
authors: Department of Immunology, Sigma-Tau S.p.A., Pomezia 00040, Italy; and.
authors: Silvia
authors: S
authors: Campo
authors: Department of Immunology, Sigma-Tau S.p.A., Pomezia 00040, Italy; and.
authors: Brunilde
authors: B
authors: Arseni
authors: Department of Immunology, Sigma-Tau S.p.A., Pomezia 00040, Italy; and.
authors: Antonio
authors: A
authors: Inforzato
authors: Department of Immunology, Sigma-Tau S.p.A., Pomezia 00040, Italy; and.
authors: Lindstedt
authors: L
authors: Ragnar
authors: Istituto Clinico Humanitas, Rozzano, Milan 20089, Italy.
authors: Barbara
authors: B
authors: Bottazzi
authors: Istituto Clinico Humanitas, Rozzano, Milan 20089, Italy.
authors: Alberto
authors: A
authors: Mantovani
authors: Department of Experimental Medicine, University of Perugia, Perugia 06132, Italy;
authors: Silvia
authors: S
authors: Moretti
authors: Department of Experimental Medicine, University of Perugia, Perugia 06132, Italy;
authors: Vasileios
authors: V
authors: Oikonomous
authors: Department of Immunology, Sigma-Tau S.p.A., Pomezia 00040, Italy; and.
authors: Rita
authors: R
authors: De Santis
authors: Department of Experimental Medicine, University of Perugia, Perugia 06132, Italy;
authors: Agostinho
authors: A
authors: Carvalho
authors: Department of Immunology, Sigma-Tau S.p.A., Pomezia 00040, Italy; and.
authors: Giovanni
authors: G
authors: Salvatori
authors: Department of Experimental Medicine, University of Perugia, Perugia 06132, Italy; luigina.romani@unipg.it.
authors: Luigina
authors: L
authors: Romani
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000276:immunology*; D000818:Animals; D001228:Aspergillosis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D001232:Aspergillus fumigatus / Q000235:genetics / Q000276:immunology*; D002097:C-Reactive Protein / Q000235:genetics / Q000276:immunology*; D057809:HEK293 Cells; D006801:Humans; D016899:Interferon-beta / Q000235:genetics / Q000276:immunology; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D051218:Lymphocyte Antigen 96 / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000276:immunology*; D000683:Serum Amyloid P-Component / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology; D000099153:Pentraxins
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D002097:C-Reactive Protein; D016899:Interferon-beta; D016753:Interleukin-10; D051218:Lymphocyte Antigen 96; D009419:Nerve Tissue Proteins; D000683:Serum Amyloid P-Component; D051197:Toll-Like Receptor 4; D000099153:Pentraxins; C508609:IL10 protein, human; C556062:IL10 protein, mouse; C495377:LY96 protein, human; C411728:Ly96 protein, mouse; C476286:Ticam1 protein, mouse; C470409:TICAM1 protein, human; C495345:TLR4 protein, human; C493487:Tlr4 protein, mouse