Department of Food Chemistry and Toxicology, Faculty of Chemistry, University of ViennaWähringer Straße 38-40, 1090 Vienna, Austria.
Core Facility Multimodal Imaging Faculty of Chemistry, University of Vienna Währinger Straße 38-40, 1090 Vienna, Austria.
Cells. 2020 Mar 31;9(4):847. doi: 10.3390/cells9040847.
The proliferation of molds in domestic environments can lead to uncontrolled continuous exposure to mycotoxins. Even if not immediately symptomatic, this may result in chronic effects, such as, for instance, immunosuppression or allergenic promotion. Alternariol (AOH) is one of the most abundant mycotoxins produced by fungi, proliferating among others in fridges, as well as in humid walls. AOH was previously reported to have immunomodulatory potential. However, molecular mechanisms sustaining this effect remained elusive. In differentiated THP-1 macrophages, AOH hardly altered the secretion of pro-inflammatory mediators when co-incubated with lipopolysaccharide (LPS), opening up the possibility that the immunosuppressive potential of the toxin could be related to an alteration of a downstream pro-inflammatory signaling cascade. Intriguingly, the mycotoxin affected the membrane fluidity in macrophages and it synergistically reacted with the cholesterol binding agent MβCD. In silico modelling revealed the potential of the mycotoxin to intercalate in cholesterol-rich membrane domains, like caveolae, and immunofluorescence showed the modified interplay of caveolin-1 with Toll-like Receptor (TLR) 4. In conclusion, we identified the structural similarity with cholesterol as one of the key determinants of the immunomodulatory potential of AOH.
室内环境中霉菌的滋生会导致对霉菌毒素的持续、不受控制的暴露。即使没有立即出现症状，也可能会导致慢性影响，例如免疫抑制或过敏原促进。交替单端孢霉烯醇（AOH）是真菌产生的最丰富的霉菌毒素之一，除其他外，它还在冰箱和潮湿的墙壁中大量繁殖。AOH 先前被报道具有免疫调节潜力。然而，维持这种效应的分子机制仍然难以捉摸。在分化的 THP-1 巨噬细胞中，AOH 与脂多糖（LPS）共同孵育时几乎不会改变促炎介质的分泌，这表明毒素的免疫抑制潜力可能与下游促炎信号级联的改变有关。有趣的是，该霉菌毒素会影响巨噬细胞中的膜流动性，并且与胆固醇结合剂 MβCD 具有协同作用。计算机模拟显示该霉菌毒素具有在富含胆固醇的膜域（如小窝）中插入的潜力，免疫荧光显示 caveolin-1 与 Toll 样受体（TLR）4 的相互作用发生改变。总之，我们确定了与胆固醇的结构相似性是 AOH 免疫调节潜力的关键决定因素之一。
