Responses to amyloids of microbial and host origin are mediated through toll-like receptor 2.
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.
Tükel
Cagla
C
Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, Davis, CA 95616-8645, USA.
Wilson
R Paul
RP
Nishimori
Jessalyn H
JH
Pezeshki
Milad
M
Chromy
Brett A
BA
Bäumler
Andreas J
AJ
D019943:Amino Acid Substitution / Q000235:genetics; D000682:Amyloid / Q000276:immunology*; D016229:Amyloid beta-Peptides / Q000276:immunology*; D000818:Animals; D001426:Bacterial Proteins / Q000276:immunology*; D002478:Cells, Cultured; D005260:Female; D020869:Gene Expression Profiling; D008264:Macrophages / Q000276:immunology; D051379:Mice; D017628:Microglia / Q000276:immunology; D016297:Mutagenesis, Site-Directed; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D010446:Peptide Fragments / Q000276:immunology*; D018805:Sepsis / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000276:immunology*
D000682:Amyloid; D016229:Amyloid beta-Peptides; D001426:Bacterial Proteins; D010446:Peptide Fragments; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; C075222:amyloid beta-protein (1-42); C077481:Crl protein, Bacteria; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse