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Methylated BSA Mimics Amyloid-Related Proteins and Triggers Inflammation

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 c...

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Autores principales: Di Domizio, Jeremy, Dorta-Estremera, Stephanie, Cao, Wei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3641125/
https://www.ncbi.nlm.nih.gov/pubmed/23650555
http://dx.doi.org/10.1371/journal.pone.0063214
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author Di Domizio, Jeremy
Dorta-Estremera, Stephanie
Cao, Wei
author_facet Di Domizio, Jeremy
Dorta-Estremera, Stephanie
Cao, Wei
author_sort Di Domizio, Jeremy
collection PubMed
description 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.
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spelling pubmed-36411252013-05-06 Methylated BSA Mimics Amyloid-Related Proteins and Triggers Inflammation Di Domizio, Jeremy Dorta-Estremera, Stephanie Cao, Wei PLoS One Research Article 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. Public Library of Science 2013-05-01 /pmc/articles/PMC3641125/ /pubmed/23650555 http://dx.doi.org/10.1371/journal.pone.0063214 Text en © 2013 Di Domizio et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Di Domizio, Jeremy
Dorta-Estremera, Stephanie
Cao, Wei
Methylated BSA Mimics Amyloid-Related Proteins and Triggers Inflammation
title Methylated BSA Mimics Amyloid-Related Proteins and Triggers Inflammation
title_full Methylated BSA Mimics Amyloid-Related Proteins and Triggers Inflammation
title_fullStr Methylated BSA Mimics Amyloid-Related Proteins and Triggers Inflammation
title_full_unstemmed Methylated BSA Mimics Amyloid-Related Proteins and Triggers Inflammation
title_short Methylated BSA Mimics Amyloid-Related Proteins and Triggers Inflammation
title_sort methylated bsa mimics amyloid-related proteins and triggers inflammation
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3641125/
https://www.ncbi.nlm.nih.gov/pubmed/23650555
http://dx.doi.org/10.1371/journal.pone.0063214
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