title: Synergy between ficolin-2 and pentraxin 3 boosts innate immune recognition and complement deposition.
abstract: The long pentraxin 3 (PTX3) is a multifunctional soluble pattern recognition molecule that is crucial in innate immune protection against opportunistic fungal pathogens such as Aspergillus fumigatus. The mechanisms that mediate downstream effects of PTX3 are largely unknown. However, PTX3 interacts with C1q from the classical pathway of the complement. The ficolins are recognition molecules of the lectin complement pathway sharing structural and functional characteristics with C1q. Thus, we investigated whether the ficolins (Ficolin-1, -2, and -3) interact with PTX3 and whether the complexes are able to modulate complement activation on A. fumigatus. Ficolin-2 could be affinity-isolated from human plasma on immobilized PTX3. In binding studies, Ficolin-1 and particularly Ficolin-2 interacted with PTX3 in a calcium-independent manner. Ficolin-2, but not Ficolin-1 and Ficolin-3, bound A. fumigatus directly, but this binding was enhanced by PTX3 and vice versa. Ficolin-2-dependent complement deposition on the surface of A. fumigatus was enhanced by PTX3. A polymorphism in the FCN2 gene causing a T236M amino acid change in the fibrinogen-like binding domain of Ficolin-2, which affects the binding to GlcNAc, reduced Ficolin-2 binding to PTX3 and A. fumigatus significantly. These results demonstrate that PTX3 and Ficolin-2 may recruit each other on pathogens. The effect was alleviated by a common amino acid change in the fibrinogen-like domain of Ficolin-2. Thus, components of the humoral innate immune system, which activate different complement pathways, cooperate and amplify microbial recognition and effector functions.
authors.affiliation: Laboratory of Molecular Medicine, Department of Clinical Immunology, Section 7631, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, Copenhagen 2100, Denmark.
authors.forename: Ying Jie
authors.initials: YJ
authors.lastname: Ma
authors.affiliation: Istituto Clinico Humanitas, Rozzano 20089, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Doni
authors.affiliation: Laboratory of Molecular Medicine, Department of Clinical Immunology, Section 7631, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, Copenhagen 2100, Denmark.
authors.forename: Tina
authors.initials: T
authors.lastname: Hummelshøj
authors.affiliation: Laboratory of Molecular Medicine, Department of Clinical Immunology, Section 7631, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, Copenhagen 2100, Denmark.
authors.forename: Christian
authors.initials: C
authors.lastname: Honoré
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, Mario Negri Institute for Pharmacological Research, Milan 20157, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Bastone
authors.affiliation: Istituto Clinico Humanitas, Rozzano 20089, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Mantovani
authors.affiliation: Laboratoire d'Enzymologie Moléculaire, Institut de Biologie Structurale Jean-Pierre Ebel, UMR 5075, CNRS-CEA-Université Joseph Fourier, Grenoble 5075, France.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Thielens
authors.affiliation: Laboratory of Molecular Medicine, Department of Clinical Immunology, Section 7631, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, Copenhagen 2100, Denmark. Electronic address: garred@post5.tele.dk.
authors.forename: Peter
authors.initials: P
authors.lastname: Garred
mesh_terms: D000818:Animals; D001232:Aspergillus fumigatus / Q000276:immunology / Q000472:pathogenicity; D002097:C-Reactive Protein / Q000235:genetics / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D015922:Complement C1q / Q000276:immunology; D003165:Complement System Proteins / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D037102:Lectins / Q000097:blood / Q000235:genetics / Q000276:immunology* / Q000302:isolation & purification; D011994:Recombinant Proteins / Q000097:blood / Q000235:genetics / Q000276:immunology / Q000302:isolation & purification; D000683:Serum Amyloid P-Component / Q000235:genetics / Q000378:metabolism*; D000097604:Ficolins; D000099153:Pentraxins
chemical_list: D002097:C-Reactive Protein; D002118:Calcium; D015922:Complement C1q; D003165:Complement System Proteins; D037102:Lectins; D011994:Recombinant Proteins; D000683:Serum Amyloid P-Component; D000097604:Ficolins; D000099153:Pentraxins