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Activation of innate immunity by lysozyme fibrils is critically dependent on cross-β sheet structure

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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.

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Abbreviations

Aβ:

Amyloid β

ASC:

Apoptosis speck-like protein containing a caspase-recruitment domain

BMDM:

Bone marrow-derived macrophage

FTIR:

Fourier-transformed infrared spectroscopy

IL-1β:

Interleukin-1β

LPS:

Lipopolysaccharide

NF-κB:

Nuclear factor-kappa B

NLR:

Nucleotide oligomerization domain-like receptor

NLRP3:

NLR, pyrin domain containing 3

PMA:

Phorbol 12-myristate 13-acetate

PRR:

Pattern-recognition receptor

TEM:

Transmission electron microscopy

ThT:

Thioflavin T

TLR:

Toll-like receptor

TNF-α:

Tumor necrosis factor-α

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Acknowledgments

The authors thank Dr. Emilie Cerf for critical reading of the manuscript and Dr. Rabia Sarroukh for helpful comments and discussion. CL is a Postdoctoral Researcher, MD and VR are Senior Research Associates at the Belgian National Fund for Scientific Research (F.R.S. - FNRS). This work was in part supported by the Belgian Government (IAP P6/19) to MD and a BBSRC Research Development Fellowship (CEB).

Conflicts of interest

The authors declare that they have no conflict of interest.

Ethical standards

The experiments performed for this study comply with the current laws of Belgium and United Kingdom.

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Authors and Affiliations

  1. Laboratory of Structure and Function of Biological Membranes, Université Libre de Bruxelles (ULB), 1050, Brussels, Belgium

    Adelin Gustot, Vincent Raussens, Jean-Marie Ruysschaert & Caroline Lonez

  2. Laboratory of Enzymology and Protein Folding, Centre for Protein Engineering, University of Liège, 4000, Liege, Belgium

    Morgane Dehousse & Mireille Dumoulin

  3. Department of Veterinary Medicine, University of Cambridge, Cambridge, CB3 OES, UK

    Clare E. Bryant & Caroline Lonez

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  1. Adelin Gustot
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  2. Vincent Raussens
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  3. Morgane Dehousse
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Correspondence to Adelin Gustot.

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Gustot, A., Raussens, V., Dehousse, M. et al. Activation of innate immunity by lysozyme fibrils is critically dependent on cross-β sheet structure. Cell. Mol. Life Sci. 70, 2999–3012 (2013). https://doi.org/10.1007/s00018-012-1245-5

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