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.
Highlights
Aspergillus fumigatus is an opportunistic fungus that causes infections under specific conditions, of which secondary immunodeficiency is by far the largest risk factor for the development of invasive infections [1]
In the current study we found that this anti-inflammatory property of GAG was due to its capacity to induce the potent anti-inflammatory cytokine interleukin-1 Receptor antagonist
We found that the induction of this anti-inflammatory cytokine by GAG correlates with increased fungal burden, and mice deficient for this cytokine were protected against aspergillosis
Summary
Aspergillus fumigatus is an opportunistic fungus that causes infections under specific conditions, of which secondary immunodeficiency is by far the largest risk factor for the development of invasive infections [1]. In order to initiate an effective host response against Aspergillus, recognition of conserved pathogen associated molecular patterns (PAMPs) by specific pattern recognition receptors (PRRs) is required. A. fumigatus has a complex cell wall consisting of polysaccharides that play essential biological functions in fungal cell biology and host-pathogen interactions. Some of these polysaccharides are recognized by various PRRs expressed on human immune cells [2]. Aspergillus expresses surface molecules that shield PAMPs or can modulate TLR responses [3]. Several surface molecules and PAMPs of A. fumigatus have been characterized as being capable of modulating or suppressing the immune response. B-glucan, a-glucan and galactomannan (GM) have been shown to modulate the host immune response [6]
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