All Title Author
Keywords Abstract

PLOS ONE  2013 

Methylated BSA Mimics Amyloid-Related Proteins and Triggers Inflammation

DOI: 10.1371/journal.pone.0063214

Full-Text   Cite this paper   Add to My Lib

Abstract:

The mechanistic study of inflammatory or autoimmune diseases requires the generation of mouse models that reproduce the alterations in immune responses observed in patients. Methylated bovine serum albumin (mBSA) has been widely used to induce antigen-specific inflammation in targeted organs or in combination with single stranded DNA (ssDNA) to generate anti-nucleic acids antibodies in vivo. However, the mechanism by which this modified protein triggers inflammation is poorly understood. By analyzing the biochemical properties of mBSA, we found that mBSA exhibits features of an intermediate of protein misfolding pathway. mBSA readily interact with a list of dyes that have binding specificity towards amyloid fibrils. Intriguingly, mBSA displayed cytotoxic activity and its binding to ssDNA further enhanced formation of beta-sheet rich amyloid fibrils. Moreover, mBSA is recognized by the serum amyloid P, a protein unanimously associated with amyloid plaques in vivo. In macrophages, we observed that mBSA disrupted the lysosomal compartment, signaled along the NLRP3 inflammasome pathway, and activated caspase 1, which led to the production of IL-1β. In vivo, mBSA triggered rapid and prominent immune cell infiltration that is dependent on IL-1β induction. Taken together, these data demonstrate that by mimicking amyloidogenic proteins mBSA exhibits strong innate immune functions and serves as a potent adjuvant. These findings advance our understanding on the underlying mechanism of how aberrant immune responses lead to autoimmune reactions.

References

[1]  Asquith DL, Miller AM, McInnes IB, Liew FY (2009) Animal models of rheumatoid arthritis. Eur J Immunol 39: 2040–2044.
[2]  Brackertz D, Mitchell GF, Mackay IR (1977) Antigen-induced arthritis in mice. I. Induction of arthritis in various strains of mice. Arthritis Rheum 20: 841–850.
[3]  van den Berg WB, van de Putte LB, Zwarts WA, Joosten LA (1984) Electrical charge of the antigen determines intraarticular antigen handling and chronicity of arthritis in mice. J Clin Invest 74: 1850–1859.
[4]  Gilkeson GS, Grudier JP, Karounos DG, Pisetsky DS (1989) Induction of anti-double stranded DNA antibodies in normal mice by immunization with bacterial DNA. J Immunol 142: 1482–1486.
[5]  Pisetsky DS (1996) Immune Activation by Bacterial DNA: A New Genetic Code. Immunity 5: 303–310.
[6]  Plescia OJ, Braun W, Palczuk NC (1964) Production of Antibodies to Denatured Deoxyribonucleic Acid (DNA). Proc Natl Acad Sci U S A 52: 279–285.
[7]  Fuchs S, Mozes E, Stollar BD (1975) The nature of murine immune response to nucleic acids. J Immunol 114: 1287–1291.
[8]  Gilkeson GS, Ruiz P, Pippen AM, Alexander AL, Lefkowith JB, et al. (1996) Modulation of renal disease in autoimmune NZB/NZW mice by immunization with bacterial DNA. J Exp Med 183: 1389–1397.
[9]  Edgington SM, Stollar BD (1992) Immunogenicity of Z-DNA depends on the size of polynucleotide presented in complexes with methylated BSA. Molecular Immunology 29: 609–617.
[10]  Gilkeson GS, Grudier JP, Pisetsky DS (1989) The antibody response of normal mice to immunization with single-stranded DNA of various species origin. Clin Immunol Immunopathol 51: 362–371.
[11]  Wilcox BJ, Seybold VS (1982) Localization of neuronal histamine in rat brain. Neuroscience Letters 29: 105–110.
[12]  Flanders KC, Roberts AB, Ling N, Fleurdelys BE, Sporn ME (1988) Antibodies to peptide determinants in transforming growth factor.beta. and their applications. Biochemistry 27: 739–746.
[13]  Selkoe DJ (2003) Folding proteins in fatal ways. Nature 426: 900–904.
[14]  Dobson CM (2003) Protein folding and misfolding. Nature 426: 884–890.
[15]  Sideras K, Gertz M (2009) Amyloidosis. Adv Clin Chem 47: 1–44.
[16]  Salminen A, Ojala J, Suuronen T, Kaarniranta K, Kauppinen A (2008) Amyloid-β; oligomers set fire to inflammasomes and induce Alzheimer’s pathology. J Cell Mol Med 12: 2255–2262.
[17]  Heneka MT, Kummer MP, Stutz A, Delekate A, Schwartz S, et al.. (2012) NLRP3 is activated in Alzheimer/’s disease and contributes to pathology in APP/PS1 mice. Nature doi:10.1038/nature11729.
[18]  Masters SL, Dunne A, Subramanian SL, Hull RL, Tannahill GM, et al. (2010) Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1beta in type 2 diabetes. Nature Immunology 11: 897–904.
[19]  Halle A, Hornung V, Petzold GC, Stewart CR, Monks BG, et al. (2008) The NALP3 inflammasome is involved in the innate immune response to amyloid-beta. Nat Immunol 9: 857–865.
[20]  Di Domizio J, Zhang R, Stagg LJ, Gagea M, Zhuo M, et al. (2012) Binding with nucleic acids or glycosaminoglycans converts soluble protein oligomers to amyloid. J Biol Chem 287: 736–747.
[21]  Di Domizio J, Dorta-Estremera S, Gagea M, Ganguly D, Meller S, et al. (2012) Nucleic acid-containing amyloid fibrils potently induce type I interferon and stimulate systemic autoimmunity. Proc Natl Acad Sci U S A 109: 14550–14555.
[22]  Nilsson MR (2004) Techniques to study amyloid fibril formation in vitro. Methods 34: 151–160.
[23]  Sipe JD, Benson MD, Buxbaum JN, Ikeda SI, Merlini G, et al. (2010) Amyloid fibril protein nomenclature: 2010 recommendations from the nomenclature committee of the International Society of Amyloidosis. Amyloid 17: 101–104.
[24]  Khurana R, Coleman C, Ionescu-Zanetti C, Carter SA, Krishna V, et al. (2005) Mechanism of thioflavin T binding to amyloid fibrils. J Struct Biol 151: 229–238.
[25]  Bucciantini M, Giannoni E, Chiti F, Baroni F, Formigli L, et al. (2002) Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases. Nature 416: 507–511.
[26]  Lindgren M, Hammarstrom P (2010) Amyloid oligomers: spectroscopic characterization of amyloidogenic protein states. FEBS J 277: 1380–1388.
[27]  Kayed R, Sokolov Y, Edmonds B, McIntire TM, Milton SC, et al. (2004) Permeabilization of lipid bilayers is a common conformation-dependent activity of soluble amyloid oligomers in protein misfolding diseases. J Biol Chem 279: 46363–46366.
[28]  Booth DR, Sunde M, Bellotti V, Robinson CV, Hutchinson WL, et al. (1997) Instability, unfolding and aggregation of human lysozyme variants underlying amyloid fibrillogenesis. Nature 385: 787–793.
[29]  Stefani M (2010) Biochemical and biophysical features of both oligomer/fibril and cell membrane in amyloid cytotoxicity. FEBS Journal 277: 4602–4613.
[30]  Hawe A, Sutter M, Jiskoot W (2008) Extrinsic fluorescent dyes as tools for protein characterization. Pharmaceutical research 25: 1487–1499.
[31]  Baltz ML, Caspi D, Evans DJ, Rowe IF, Hind CR, et al. (1986) Circulating serum amyloid P component is the precursor of amyloid P component in tissue amyloid deposits. Clin Exp Immunol 66: 691–700.
[32]  Pepys MB, Dyck RF, de Beer FC, Skinner J, Cohen AS (1979) Binding of serum amyloid P-component (SAP) by amyloid fibrils. Clin Exp Immunol 38: 284–293.
[33]  Pepys MB, Booth DR, Hutchinson WL, Gallimore JR, Collins PM, et al. (1997) Amyloid P component. A critical review. Amyloid-International Journal of Experimental and Clinical Investigation 4: 274–295.
[34]  Hornung V, Bauernfeind F, Halle A, Samstad EO, Kono H, et al. (2008) Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat Immunol 9: 847–856.
[35]  Lamkanfi M, Mueller JL, Vitari AC, Misaghi S, Fedorova A, et al. (2009) Glyburide inhibits the Cryopyrin/Nalp3 inflammasome. J Cell Biol 187: 61–70.
[36]  Pulendran B, Ahmed R (2011) Immunological mechanisms of vaccination. Nat Immunol 12: 509–517.
[37]  Masters SL, O’Neill LA (2011) Disease-associated amyloid and misfolded protein aggregates activate the inflammasome. Trends in Molecular Medicine 17: 276–282.
[38]  Henao-Mejia J, Elinav E, Strowig T, Flavell RA (2012) Inflammasomes: far beyond inflammation. Nature Immunology 13: 321–324.
[39]  van Lent PL, Dekker C, Mosterd J, van den Bersselaar L, van den Berg WB (1989) Allergic arthritis induced by cationic proteins: role of molecular weight. Immunology 67: 447–452.
[40]  Verri WA Jr, Guerrero AT, Fukada SY, Valerio DA, Cunha TM, et al. (2008) IL-33 mediates antigen-induced cutaneous and articular hypernociception in mice. Proc Natl Acad Sci U S A 105: 2723–2728.
[41]  Whitehouse M (2012) Oily adjuvants and autoimmunity: now time for reconsideration? Lupus 21: 217–222.
[42]  Meroni PL (2011) Autoimmune or auto-inflammatory syndrome induced by adjuvants (ASIA): old truths and a new syndrome? J Autoimmun 36: 1–3.
[43]  Reeves WH, Lee PY, Weinstein JS, Satoh M, Lu L (2009) Induction of autoimmunity by pristane and other naturally occurring hydrocarbons. Trends Immunol 30: 455–464.

Full-Text

comments powered by Disqus