Mutations in the cold-induced autoinflammatory syndrome 1 (CIAS1) gene are associated with a spectrum of autoinflammatory diseases, including
familial cold autoinflammatory syndrome,
Muckle-Wells syndrome, and chronic infantile neurologic, cutaneous, articular syndrome, also known as
neonatal-onset multisystem inflammatory disease. CIAS1 encodes cryopyrin, a
protein that localizes to the cytosol and functions as
pattern recognition receptor. Cryopyrin also participates in
nuclear factor-kappaB regulation and caspase-1-mediated maturation of
interleukin 10. In this study, we showed that disease-associated mutations in CIAS1 induced rapid cell death of THP-1 monocytic cells. The features of cell death, including
7-AAD staining, the presence of cellular
edema, and early membrane damage resulting in
lactate dehydrogenase (LDH) release, indicated that it was more likely to be
necrosis than apoptosis, and was effectively blocked with the
cathepsin B-specific inhibitor CA-074-Me. CA-074-Me also suppressed induced by disease-associated mutation lysosomal leakage and mitochondrial damage. In addition,
R837, a recently identified activator of cryopyrin-associated
inflammasomes, induced cell death in wild type CIAS1-transfected THP-1 cells. These results indicated that monocytes undergo rapid cell death in a
cathepsin B-dependent manner upon activation of cryopyrin, which is also a specific phenomenon induced by disease-associated mutation of CIAS1.