title: Methylated BSA mimics amyloid-related proteins and triggers inflammation.
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.
authors: Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors: Jeremy
authors: J
authors: Di Domizio
authors: Stephanie
authors: S
authors: Dorta-Estremera
authors: Wei
authors: W
authors: Cao
mesh_terms: D000682:Amyloid / Q000737:chemistry; D058227:Amyloidogenic Proteins / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D052160:Benzothiazoles; D002352:Carrier Proteins; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D005456:Fluorescent Dyes / Q000737:chemistry; D058847:Inflammasomes / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D011485:Protein Binding; D017510:Protein Folding; D012710:Serum Albumin, Bovine / Q000737:chemistry* / Q000494:pharmacology; D000683:Serum Amyloid P-Component / Q000737:chemistry; D015398:Signal Transduction; D013844:Thiazoles / Q000737:chemistry
chemical_list: D000682:Amyloid; D058227:Amyloidogenic Proteins; D052160:Benzothiazoles; D002352:Carrier Proteins; D016207:Cytokines; D005456:Fluorescent Dyes; D058847:Inflammasomes; D018836:Inflammation Mediators; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D000683:Serum Amyloid P-Component; D013844:Thiazoles; C029180:methylated bovine serum albumin; C009462:thioflavin T; D012710:Serum Albumin, Bovine
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