A polysaccharide virulence factor from Aspergillus fumigatus elicits anti-inflammatory effects through induction of Interleukin-1 receptor antagonist

• Published in: PLoS pathogens Vol. 10; no. 3; p. e1003936
• Main Authors: Gresnigt, Mark S, Bozza, Silvia, Becker, Katharina L, Joosten, Leo A B, Abdollahi-Roodsaz, Shahla, van der Berg, Wim B, Dinarello, Charles A, Netea, Mihai G, Fontaine, Thierry, De Luca, Antonella, Moretti, Silvia, Romani, Luigina, Latge, Jean-Paul, van de Veerdonk, Frank L
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.03.2014; Public Library of Science (PLoS)
• Subjects: Animals; Aspergillosis; Aspergillosis - immunology; Aspergillus; Aspergillus fumigatus; Aspergillus fumigatus - immunology; Biology; Cellular Biology; Cytokines; Cytokines - biosynthesis; Cytokines - immunology; Disease Models, Animal; Drinking water; Enzyme-Linked Immunosorbent Assay; Experiments; Female; Fungal Polysaccharides; Fungal Polysaccharides - immunology; Grants; Health aspects; Histology; Humans; Immune system; Infections; Inflammatory bowel disease; Interleukin 1 Receptor Antagonist Protein; Interleukin 1 Receptor Antagonist Protein - biosynthesis; Interleukin 1 Receptor Antagonist Protein - immunology; Interleukin-1; Leukocytes, Mononuclear; Leukocytes, Mononuclear - immunology; Life Sciences; Medicine; Mice; Mice, Inbred BALB C; Mice, Knockout; Microbiological research; Microbiology and Parasitology; Mycology; Polysaccharides; Polysaccharides - immunology; Rodents; Virulence (Microbiology); Virulence Factors; Virulence Factors - immunology; France; United States; Cytokines; Enzyme-Linked Immunosorbent Assay; Humans; Leukocytes, Mononuclear; Fungal Polysaccharides; Virulence Factors; Mice, Knockout; Polysaccharides; Animals; Aspergillosis; Female; Interleukin 1 Receptor Antagonist Protein; Mice; Mice, Inbred BALB C; Aspergillus fumigatus; Disease Models, Animal
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1003936

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.