Matae Ahn,et al.

Bats are special in their ability to live long and host many emerging viruses.Our previous studies showed that bats have altered inflammasomes,which are central players in aging and infection.However,the role of inflammasome signaling in combating inflammatory diseases remains poorly understood.Here,we report bat ASC2 as a potent negative regulator of inflammasomes.Bat ASC2 is highly expressed at both the mRNA and protein levels and is highly potent in inhibiting human and mouse inflammasomes.Transgenic expression of bat ASC2 in mice reduced the severity of peritonitis induced by gout crystals and ASC particles.Bat ASC2 also dampened inflammation induced by multiple viruses and reduced mortality of influenza A virus infection.Importantly,it also suppressed SARS-CoV-2-immune-complex-induced inflammasome activation.Four key residues were identified for the gain of function of bat ASC2.Our results demonstrate that bat ASC2 is an important negative regulator of inflammasomes with therapeutic potential in inflammatory diseases.