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

PLoS Pathogens

Charles A. Dinarello¹  Thierry Fontaine¹  Leo A. B. Joosten¹  Katharina L. Becker¹  Mark S. Gresnigt¹  Mihai G. Netea²  Shahla Abdollahi-Roodsaz³  Wim B. van der Berg³  Luigina Romani⁴  Jean-Paul Latge⁴  Silvia Moretti⁴  Silvia Bozza⁴  Frank L. van de Veerdonk⁵  Antonella De Luca⁵ 

[1] Department of Medicine, Radboud University Medical Center, Nijmegen, The Netherlands;Department of Medicine, University of Colorado Denver, Aurora, Colorado, United States of America;Department of Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands;Microbiology Section, Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy;Unité des Aspergillus, Institut Pasteur, Paris, France

关键词: Cytokines;    Aspergillus fumigatus;    Aspergillosis;    Aspergillus;    Mouse models;    Colitis;    Immune response;    Neutrophils;   

DOI  :  10.1371/journal.ppat.1003936

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY