Tükel Cagla, Wilson R Paul, Nishimori Jessalyn H, Pezeshki Milad, Chromy Brett A, Bäumler Andreas J
Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, Davis, CA 95616-8645, USA.
Cell Host Microbe. 2009 Jul 23;6(1):45-53. doi: 10.1016/j.chom.2009.05.020.
Curli fibrils are proteinaceous bacterial structures formed by amyloid fibrils composed of the major curli subunit CsgA. Like beta-amyloid 1-42, which is associated with brain inflammation and Alzheimer's disease, curli fibrils have been implicated in the induction of host inflammatory responses. However, the underlying mechanisms of amyloid-induced inflammation are not fully understood. In a mouse sepsis model, we show that curli fibrils contributed to Nos2 expression, a hallmark of inflammation, by stimulating Toll-like receptor (TLR) 2. The TLR2 agonist activity was reduced by an amyloidogenicity-lowering amino acid substitution (N122A) in CsgA. Amyloid-forming synthetic peptides corresponding to beta-amyloid 1-42 or CsgA 111-151 stimulated Nos2 production in macrophages and microglia cells through a TLR2-dependent mechanism. This activity was abrogated when an N122A substitution was introduced into the synthetic CsgA peptide. The induction of TLR2-mediated responses by bacterial and eukaryotic amyloids may explain the inflammation associated with amyloids and the resulting pathologies.
卷曲菌毛是由主要卷曲菌毛亚基CsgA组成的淀粉样纤维形成的蛋白质性细菌结构。与脑炎症和阿尔茨海默病相关的β-淀粉样蛋白1-42一样，卷曲菌毛也与宿主炎症反应的诱导有关。然而，淀粉样蛋白诱导炎症的潜在机制尚未完全了解。在小鼠脓毒症模型中，我们发现卷曲菌毛通过刺激Toll样受体（TLR）2促进了炎症标志物Nos2的表达。CsgA中降低淀粉样变性的氨基酸替代（N122A）降低了TLR2激动剂活性。与β-淀粉样蛋白1-42或CsgA 111-151相对应的形成淀粉样蛋白的合成肽通过TLR2依赖性机制刺激巨噬细胞和小胶质细胞中Nos2的产生。当在合成的CsgA肽中引入N122A替代时，这种活性被消除。细菌和真核淀粉样蛋白对TLR2介导反应的诱导可能解释了与淀粉样蛋白相关的炎症以及由此产生的病理状况。
