A polysaccharide virulence factor from Aspergillus fumigatus elicits anti-inflammatory effects through induction of Interleukin-1 receptor antagonist.
A polysaccharide virulence factor from Aspergillus fumigatus elicits anti-inflammatory effects through induction of Interleukin-1 receptor antagonist.
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DOI：
10.1371/journal.ppat.1003936
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发表时间：
2014-03
期刊：
影响因子：
6.7
通讯作者：
van de Veerdonk FL
中科院分区：
文献类型：
--
作者：
Gresnigt MS;Bozza S;Becker KL;Joosten LA;Abdollahi-Roodsaz S;van der Berg WB;Dinarello CA;Netea MG;Fontaine T;De Luca A;Moretti S;Romani L;Latge JP;van de Veerdonk FL
半乳糖胺半乳聚糖（GAG）是烟曲霉的细胞壁成分，在小鼠中具有强效抗炎作用。然而，负责GAG的抗炎特性的机制仍有待阐明。在本研究中，我们使用体外PBMC刺激试验证明，GAG通过诱导白细胞介素-1受体拮抗剂（IL-1 Ra）（一种阻断IL-1信号传导的强效抗炎细胞因子）抑制人PBMC中促炎性辅助性T细胞（Th）1和Th 17细胞因子的产生。在存在抗IL-1 Ra中和抗体的情况下，GAG不能抑制人辅助性T细胞因子的产生。在侵袭性曲霉病的小鼠模型中，GAG在体内诱导IL-1 Ra，并且在IL-1 Ra缺乏的小鼠中未观察到野生型小鼠中存在GAG时对侵袭性曲霉病的易感性增加。此外，我们证明了GAG诱导IL-1 Ra的能力也可用于治疗炎性疾病，因为GAG能够降低过敏性曲霉病实验模型和小鼠DSS诱导的结肠炎模型的严重程度。在侵袭性曲霉病的情况下，GAG通过诱导IL-1 Ra具有显著的免疫调节功能，并且特别地，IL-1 Ra敲除小鼠对侵袭性肺曲霉病完全保护。这为在急性侵袭性真菌感染的背景下靶向IL-1 Ra开辟了新的治疗策略。然而，GAG还可以保护小鼠免受变态反应和结肠炎的观察结果使得GAG或GAG的衍生结构成为用于IL-1驱动的炎性疾病的潜在治疗化合物。 烟曲霉是一种机会致病真菌，主要引起免疫功能低下的宿主感染。已知曲霉菌采用各种策略来逃避宿主免疫系统的免疫识别。最近，半乳糖胺半乳聚糖（GAG），曲霉细胞壁的一种新成分，被发现在小鼠中具有有效的抗炎作用，使它们更容易患上曲霉病。在目前的研究中，我们发现GAG的这种抗炎特性是由于其诱导强效抗炎细胞因子白细胞介素-1受体拮抗剂的能力。这种细胞因子干扰IL-1信号传导，从而可以减少IL-1诱导的免疫应答，如T细胞应答。我们还发现，GAG诱导的这种抗炎细胞因子与真菌负荷增加相关，缺乏这种细胞因子的小鼠可预防曲霉病。此外，我们表明，GAG诱导IL-1信号传导的天然调节因子的能力可用于治疗IL-1介导的疾病，如过敏和结肠炎。我们的研究为GAG的免疫调节活性提供了新的见解，并开辟了利用GAG作为炎性疾病治疗的抗炎潜力的可能性。
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. Aspergillus fumigatus is an opportunistic pathogenic fungus that primarily causes infections in the immunocompromised host. It is known that Aspergillus employs various strategies to evade immune recognition by the host's immune system. Recently, galactosaminogalactan (GAG), a new component of the Aspergillus cell wall, was discovered to have potent anti-inflammatory effects in mice making them more susceptible to Aspergillosis. 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. This cytokine interferes with IL-1 signalling and thereby can reduce IL-1–induced immune responses such as T-cell responses. We also 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. Additionally, we show that the capacity of GAG to induce the natural regulator of IL-1 signalling could be used in the treatment of IL-1–mediated disease such as allergy and colitis. Our study provides new insights on the immunoregulatory activity of GAG and opens up possibilities to exploit the anti-inflammatory potential of GAG as a therapy for inflammatory diseases.
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影响因子：
6.7
作者：
Gravelat FN;Beauvais A;Liu H;Lee MJ;Snarr BD;Chen D;Xu W;Kravtsov I;Hoareau CM;Vanier G;Urb M;Campoli P;Al Abdallah Q;Lehoux M;Chabot JC;Ouimet MC;Baptista SD;Fritz JH;Nierman WC;Latgé JP;Mitchell AP;Filler SG;Fontaine T;Sheppard DC
通讯作者：
Sheppard DC
影响因子：
9.1
作者：
Sainz, J.;Perez, E.;Jurado, M.
通讯作者：
Jurado, M.
影响因子：
20.3
作者：
Marr, KA;Carter, RA;Corey, L
通讯作者：
Corey, L
DOI：
10.1073/pnas.0902745106
发表时间：
2009-04-28
影响因子：
11.1
作者：
Ben-Sasson, Shlomo Z.;Hu-Li, Jane;Paul, William E.
通讯作者：
Paul, William E.
DOI：
10.1056/nejmoa0807865
发表时间：
2009-06-04
期刊：
The New England journal of medicine
影响因子：
--
作者：
Aksentijevich I;Masters SL;Ferguson PJ;Dancey P;Frenkel J;van Royen-Kerkhoff A;Laxer R;Tedgård U;Cowen EW;Pham TH;Booty M;Estes JD;Sandler NG;Plass N;Stone DL;Turner ML;Hill S;Butman JA;Schneider R;Babyn P;El-Shanti HI;Pope E;Barron K;Bing X;Laurence A;Lee CC;Chapelle D;Clarke GI;Ohson K;Nicholson M;Gadina M;Yang B;Korman BD;Gregersen PK;van Hagen PM;Hak AE;Huizing M;Rahman P;Douek DC;Remmers EF;Kastner DL;Goldbach-Mansky R
通讯作者：
Goldbach-Mansky R