The ASC inflammasome adapter controls the extent of peripheral protein aggregate deposition in inflammation-associated amyloidosis

Abstract

The apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) protein is a component of inflammasomes, inflammation-mediating complexes that include Nucleotide-Binding Oligomerization Domain, Leucine Rich Repeat And Pyrin Domain Containing 3 (NLRP3). ASC and NLRP3 components aggregate to form ASC specks, which can cross-seed Aβ aggregation in Alzheimer’s disease (AD). Here we asked whether ASC is involved in additional protein misfolding diseases (PMDs). AA amyloidosis is a severe complication of chronic inflammatory conditions caused by the aggregation of Serum Amyloid A (SAA) protein. Since AA and Aβ aggregates share similar biochemical properties, such as β-sheet structures, we hypothesized that ASC inflammasomes may be involved in SAA/AA recruitment, aggregation, processing and removal. We therefore investigated the role of ASC in AA amyloidosis in vivo, employing a murine AA amyloidosis model in Asc-ablated mice. We show that ASC exerts a crucial role in SAA recruitment in the presence of AA fibrils, that splenic AA amyloid load was decreased in Asc-/- mice, that the presence of ASC accelerates SAA fibril formation and that ASC is important for SAA-activated phagocytosis of macrophages. We conclude that ASC modulates both SAA serum levels and the severity of AA amyloidosis in mice. ASC may represent a therapeutic target in AA as well as other amyloidosis entities.

The Cystic Fibrosis Transmembrane Regulator Controls Tolerogenic Responses to Food Allergens in Mice and Humans

“…Conversely, they can point to their association with absence of disease. We have investigated the antibody repertoires of large collections of patients for the occurrence of autoantibodies against the prion protein (Senatore et al, 2020), the tau microtubule-binding domain (Magalhães et al, 2021), and apoptosis-associated speck-like protein containing a CARD (Losa et al, 2023), and have studied seroepidemiological correlations of immune reactivity to SARS-CoV-2 proteins in 72,250 plasma samples of 54,153 individuals (Emmenegger, De Cecco, et al, 2023).…”