title: Activation of innate immunity by lysozyme fibrils is critically dependent on cross-β sheet structure.
abstract: Inflammation occurs in many amyloidoses, but its underlying mechanisms remain enigmatic. Here we show that amyloid fibrils of human lysozyme, which are associated with severe systemic amyloidoses, induce the secretion of pro-inflammatory cytokines through activation of the NLRP3 (NLR, pyrin domain containing 3) inflammasome and the Toll-like receptor 2, two innate immune receptors that may be involved in immune responses associated to amyloidoses. More importantly, our data clearly suggest that the induction of inflammatory responses by amyloid fibrils is linked to their intrinsic structure, because the monomeric form and a non-fibrillar type of lysozyme aggregates are both unable to trigger cytokine secretion. These lysozyme species lack the so-called cross-β structure, a characteristic structural motif common to all amyloid fibrils irrespective of their origin. Since fibrils of other bacterial and endogenous proteins have been shown to trigger immunological responses, our observations suggest that the cross-β structural signature might be recognized as a generic danger signal by the immune system.
authors: Laboratory of Structure and Function of Biological Membranes, Université Libre de Bruxelles (ULB), Brussels, Belgium. adelingustot@hotmail.com
authors: Adelin
authors: A
authors: Gustot
authors: Vincent
authors: V
authors: Raussens
authors: Morgane
authors: M
authors: Dehousse
authors: Mireille
authors: M
authors: Dumoulin
authors: Clare E
authors: CE
authors: Bryant
authors: Jean-Marie
authors: JM
authors: Ruysschaert
authors: Caroline
authors: C
authors: Lonez
mesh_terms: D000682:Amyloid / Q000276:immunology* / Q000378:metabolism; D000686:Amyloidosis / Q000276:immunology / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D058847:Inflammasomes / Q000276:immunology / Q000378:metabolism; D007249:Inflammation / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D053583:Interleukin-1beta / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009113:Muramidase / Q000276:immunology* / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D017433:Protein Structure, Secondary; D051195:Toll-Like Receptor 2 / Q000276:immunology / Q000378:metabolism
chemical_list: D000682:Amyloid; D002352:Carrier Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D009113:Muramidase