Inflammasomes are
multiprotein complexes that trigger the activation of caspase-1 and the maturation of IL-1β, which are critical for
inflammation and control of pathogen
infection. Although the function of
inflammasomes in immune response and disease development is well studied, the molecular mechanism by which
inflammasomes are activated and assembled remains largely unknown. In this study, we found that β-arrestin1, a key regulator of the
G protein-coupled receptor signaling pathway, was required for
nucleotide-binding domain and
leucine-rich repeat containing (NLR) family pyrin domain-containing 3 (NLRP3) and NLR family CARD domain-containing
protein 4 (NLRC4)
inflammasome-mediated IL-1β production and caspase-1 activation, but it had no effect on absent in
melanoma 2 (AIM2)
inflammasome activation. Moreover, apoptosis-associated speck-like
protein containing a CARD (ASC)
pyroptosome, which is ASC aggregation mediating caspase-1 activation, was also impaired in β-arrestin1-deficient macrophages upon NLRP3 or NLRC4, but not AIM2
inflammasome activation. Mechanistic study revealed that β-arrestin1 specifically interacted with NLRP3 and NLRC4 and promoted their self-oligomerization. In vivo, in a
monosodium urate crystal (MSU)-induced NLRP3-dependent
peritonitis model, MSU-induced IL-1β production and neutrophil flux were significantly reduced in β-arrestin1 knockout mice. Additionally, β-arrestin1 deficiency rescued the
weight loss of mice upon log-phase Salmonella typhimurium
infection, with less IL-1β production. Taken together, our results indicate that β-arrestin1 plays a critical role in the assembly and activation of two major canonical
inflammasomes, and it may provide a new therapeutic target for inflammatory diseases.