Journal Article

The ASC inflammasome adapter governs SAA-derived protein aggregation in inflammatory amyloidosis

Losa, Marco, Lysenko, Veronika, Emmenegger, Marc, Carta, Manfredi C, Frontzek, Karl J, Nilsson, K Peter R, Aguzzi, Adriano, Pengo, Niccolò, Hornemann, Simone, Picotti, Paola, Westermark, Gunilla T, Bieli, Dimitri, Schürch, Patrick M, Capron, Danaëlle, Rupp, Niels J, Theocharides, Alexandre PA, De Rossi, Pierre, Polymenidou, Magdalini, Serdiuk, Tetiana, Reimann, Regina R, Nuvolone, Mario, Bargenda, Niklas, Schwarz, Petra

2024

Overview

Extracellularly released molecular inflammasome assemblies -ASC specks- cross-seed Aβ amyloid in Alzheimer’s disease. Here we show that ASC governs the extent of inflammation-induced amyloid A (AA) amyloidosis, a systemic disease caused by the aggregation and peripheral deposition of the acute-phase reactant serum amyloid A (SAA) in chronic inflammatory conditions. Using super-resolution microscopy, we found that ASC colocalized tightly with SAA in human AA amyloidosis. Recombinant ASC specks accelerated SAA fibril formation and mass spectrometry after limited proteolysis showed that ASC interacts with SAA via its pyrin domain (PYD). In a murine model of inflammatory AA amyloidosis, splenic amyloid load was conspicuously decreased in Pycard −/− mice which lack ASC. Treatment with anti-ASC PYD antibodies decreased amyloid loads in wild-type mice suffering from AA amyloidosis. The prevalence of natural anti-ASC IgG (−logEC 50  ≥ 2) in 19,334 hospital patients was <0.01%, suggesting that anti-ASC antibody treatment modalities would not be confounded by natural autoimmunity. These findings expand the role played by ASC and IL-1 independent inflammasome employments to extraneural proteinopathies and suggest that anti-ASC immunotherapy may contribute to resolving such diseases. Synopsis ASC scaffolds and cross-seeds Aβ amyloid and is considered an actionable target against Alzheimer’s disease. This study investigated the role of ASC in amyloid A (AA) amyloidosis, a systemic disease in which serum amyloid A (SAA) aggregates invade internal organs due to chronic inflammation. ASC and SAA were found to colocalize in inflammatory amyloidosis in humans and mice. ASC interacts with SAA via its pyrin domain (PYD) and was found to accelerate SAA/AA fibril formation in a dose-dependent manner. Ablation of Pycard ( Asc ) was found to reduce amyloid deposition in mice. Immunotherapy with an anti-ASC antibody targeting the PYD diminished SAA-derived amyloid deposition and its sequelae in vivo. A large-scale human anti-ASC autoantibody screening of 23,450 plasma samples from 19,334 patients revealed rare immunoreactivity towards ASC, indicating high tolerance for employing anti-ASC modalities in inflammatory diseases. ASC scaffolds and cross-seeds Aβ amyloid and is considered an actionable target against Alzheimer’s disease. This study investigated the role of ASC in amyloid A (AA) amyloidosis, a systemic disease in which serum amyloid A (SAA) aggregates invade internal organs due to chronic inflammation.

• Publisher: Nature Publishing Group UK,Springer Nature
• Subject: Amyloidosis / Amyloidosis - metabolism / Amyloidosis - pathology / Animals / ASC / Biomedical and Life Sciences / Biomedicine / CARD Signaling Adaptor Proteins - genetics / CARD Signaling Adaptor Proteins - metabolism / Disease Models, Animal / EMBO19 / Humans / Inflammasomes - metabolism / Inflammation / Inflammation - metabolism / Inflammation - pathology / Innate Immunity / Mice / Mice, Inbred C57BL / Mice, Knockout / Molecular Medicine / Protein Aggregates / Serum Amyloid A (SAA) / Serum Amyloid A Protein - metabolism