title: A polysaccharide virulence factor from Aspergillus fumigatus elicits anti-inflammatory effects through induction of Interleukin-1 receptor antagonist.
abstract: The galactosaminogalactan (GAG) is a cell wall component of Aspergillus fumigatus that has potent anti-inflammatory effects in mice. However, the mechanisms responsible for the anti-inflammatory property of GAG remain to be elucidated. In the present study we used in vitro PBMC stimulation assays to demonstrate, that GAG inhibits proinflammatory T-helper (Th)1 and Th17 cytokine production in human PBMCs by inducing Interleukin-1 receptor antagonist (IL-1Ra), a potent anti-inflammatory cytokine that blocks IL-1 signalling. GAG cannot suppress human T-helper cytokine production in the presence of neutralizing antibodies against IL-1Ra. In a mouse model of invasive aspergillosis, GAG induces IL-1Ra in vivo, and the increased susceptibility to invasive aspergillosis in the presence of GAG in wild type mice is not observed in mice deficient for IL-1Ra. Additionally, we demonstrate that the capacity of GAG to induce IL-1Ra could also be used for treatment of inflammatory diseases, as GAG was able to reduce severity of an experimental model of allergic aspergillosis, and in a murine DSS-induced colitis model. In the setting of invasive aspergillosis, GAG has a significant immunomodulatory function by inducing IL-1Ra and notably IL-1Ra knockout mice are completely protected to invasive pulmonary aspergillosis. This opens new treatment strategies that target IL-1Ra in the setting of acute invasive fungal infection. However, the observation that GAG can also protect mice from allergy and colitis makes GAG or a derivative structure of GAG a potential treatment compound for IL-1 driven inflammatory diseases.
authors.affiliation: Department of Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Gresnigt
authors.affiliation: Microbiology Section, Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Bozza
authors.affiliation: Department of Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Katharina L
authors.initials: KL
authors.lastname: Becker
authors.affiliation: Department of Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Leo A B
authors.initials: LA
authors.lastname: Joosten
authors.affiliation: Department of Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Shahla
authors.initials: S
authors.lastname: Abdollahi-Roodsaz
authors.affiliation: Department of Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Wim B
authors.initials: WB
authors.lastname: van der Berg
authors.affiliation: Department of Medicine, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Medicine, University of Colorado Denver, Aurora, Colorado, United States of America.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Dinarello
authors.affiliation: Department of Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
authors.affiliation: Unité des Aspergillus, Institut Pasteur, Paris, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Fontaine
authors.affiliation: Microbiology Section, Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: De Luca
authors.affiliation: Microbiology Section, Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Moretti
authors.affiliation: Microbiology Section, Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy.
authors.forename: Luigina
authors.initials: L
authors.lastname: Romani
authors.affiliation: Unité des Aspergillus, Institut Pasteur, Paris, France.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Latge
authors.affiliation: Department of Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Frank L
authors.initials: FL
authors.lastname: van de Veerdonk
mesh_terms: D000818:Animals; D001228:Aspergillosis / Q000276:immunology*; D001232:Aspergillus fumigatus / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D062610:Fungal Polysaccharides / Q000276:immunology*; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000096:biosynthesis* / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011134:Polysaccharides / Q000276:immunology*; D037521:Virulence Factors / Q000276:immunology*
chemical_list: D016207:Cytokines; D062610:Fungal Polysaccharides; D053590:Interleukin 1 Receptor Antagonist Protein; D011134:Polysaccharides; D037521:Virulence Factors; C062157:galactosaminogalactan