Expression of ASC in Renal Tissues of Familial Mediterranean Fever Patients with Amyloidosis: Postulating a Role for ASC in AA Type Amyloid Deposition

Abstract

Familial Mediterranean fever (FMF) is characterized by recurrent attacks of fever and serositis; in some cases, ensuing amyloidosis results in kidney damage. Treatment with colchicine reduces the frequency and severity of FMF attacks and prevents amyloidosis, although the mechanisms behind these effects are unknown. Pyrin, the protein product of the MEFV gene, interacts with ASC, a key molecule in apoptotic and inflammatory processes. ASC forms intracellular speck-like aggregates that presage cell death. Here we show that cell death after ASC speck formation is much slower in nonmyeloid cells than in myeloid cells. Additionally, we demonstrate that colchicine prevents speck formation and show that specks can survive in the extracellular space after cell death. Because we also found that ASC is expressed in renal glomeruli of patients with FMF but not in those of control patients, we posit that high local ASC expression may result in speck formation and that specks from dying cells may persist in the extracellular space where they have the potential (perhaps in association with pyrin) to nucleate amyloid. The fact that speck formation requires an intact microtubule network as shown here could potentially account for the ability of prophylactic colchicine to prevent or reverse amyloidosis in patients with FMF.

The NLRP3 inflammasome is released as a particulate danger signal that amplifies the inflammatory response

“…Here we found that caspase-1 controlled the release of inflammasome particles from macrophages at very early time points after the activation of inflammasomes (10-30 min after activation with ATP or nigericin), with an insignificant increase in extracellular LDH but with enhanced membrane permeabilization. Similarly, death induced in COS-7 monkey kidney cells by overexpression of ASC also leads to the presence of stable extracellular ASC specks 31 . LDH is a cytosolic protein with a molecular mass of 140 kDa and a diameter of 26.6 nm that is routinely used to monitor cell death; it is smaller than inflammasome particles (1-2 µm in diameter) 9 , which suggests that pyroptosis might 'preferentially' result in the release of specific cytosolic components.…”

Kinetic properties of ASC protein aggregation in epithelial cells

“…Both form near the nucleus, co-localizing with the MTOC (Lee et al, 2002;Balci-Peynircioglu et al, 2008). Interference with the microtubule network of the cell by treatment with nocodozole inhibits speck formation (Balci-Peynircioglu et al, 2008) and also prevents aggresome formation (Johnston et al, 1998).…”

“…Since the majority of specks are localized near the microtubuleorganizing center (MTOC), and since treatment of cells with the microtubule toxin nocodazole prevents ASC speck formation (Balci-Peynircioglu et al, 2008), motor proteins moving ASC molecules along microtubules seem to be an attractive possibility. Given the narrow range of parameters that can predict the kinetics of speck formation from diffusion, we considered whether active transport of ASC proteins might play a role during ASC speck formation (see Supporting Information for a detailed discussion).…”

The intra‐ and extracellular functions of ASC specks

“…IL‐1β enhances the expansion, effector function, and the protective value of weak antigens . The accumulation of extracellular and bioactive ASC specks in tissues, such as the kidneys, or lymph nodes (LNs), could alter the cytokine milieu and substantially skew effector T‐cell differentiation, proliferation, and effector function. This theory is supported by the study of Sagoo and coleagues, who demonstrated in the context of viral infection that modified vaccinia Ankara virus (MVA)‐induced pyroptosis of subcapsular sinus macrophages in the LNs, which released ASC specks.…”