Journal Article

A Polysaccharide Virulence Factor from Aspergillus fumigatus Elicits Anti-inflammatory Effects through Induction of Interleukin-1 Receptor Antagonist

Romani, Luigina, Gresnigt, Mark S., Joosten, Leo A. B., Becker, Katharina L., Abdollahi-Roodsaz, Shahla, Moretti, Silvia, Netea, Mihai G., Dinarello, Charles A., Bozza, Silvia, van de Veerdonk, Frank L., Latge, Jean-Paul, van der Berg, Wim B., Fontaine, Thierry, De Luca, Antonella

2014

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: 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