The ASC inflammasome adapter controls the severity of inflammation-related AA amyloidosis

ASC-containing inflammasomes form specks, extracellular aggregates which enhance the aggregation of Aβ amyloid in Alzheimer’s disease. This raises the question whether ASC participates to additional aggregation proteinopathies. Here we show that ASC controls the extent of inflammation-related AA amyloidosis, a systemic disease caused by the aggregation of the acute-phase reactant serum amyloid A (SAA). Using superresolution microscopy, we found that ASC colocalized tightly with SAA in human AA amyloidosis. Purified recombinant ASC specks accelerated SAA fibril formation in vitro . Mass spectrometry after limited proteolysis showed that ASC interacts with SAA via its pyrin domain. In a murine model of inflammation-related AA amyloidosis, splenic AA amyloid load was conspicuously decreased in Pycard ^{tm1Vmd/tm1Vmd} mice which lack ASC. This reduction was not a consequence of enhanced amyloid phagocytosis, as SAA stimulation increased phagocytic activity in Asc ^+/+ , but not in Asc ^-/- macrophages. Treatment with anti-ASC antibodies decreased the amyloid loads and attenuated the body-weight loss of 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 to extraneural proteinopathies of humans and experimental animals and suggest that anti-ASC immunotherapy may contribute to resolving such diseases.