Bat ASC2 suppresses inflammasomes and ameliorates inflammatory diseases

• Published in: Cell Vol. 186; no. 10; pp. 2144 - 2159.e22
• Main Authors: Ahn, Matae, Chen, Vivian Chih-Wei, Rozario, Pritisha, Ng, Wei Lun, Kong, Pui San, Sia, Wan Rong, Kang, Adrian Eng Zheng, Su, Qi, Nguyen, Lan Huong, Zhu, Feng, Chan, Wharton O.Y., Tan, Chee Wah, Cheong, Wan Shoo, Hey, Ying Ying, Foo, Randy, Guo, Fusheng, Lim, Yan Ting, Li, Xin, Chia, Wan Ni, Sobota, Radoslaw M., Fu, Nai Yang, Irving, Aaron T., Wang, Lin-Fa
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11.05.2023
• Subjects: Animals; Apoptosis Regulatory Proteins - metabolism; bats; Chiroptera - immunology; COVID-19; disease resistance; Humans; immune complex; inflammasome; Inflammasomes - immunology; inflammation; inflammatory diseases; longevity; Mice; Ribonucleoproteins - metabolism; SARS-CoV-2; viral reservoir; Virus Diseases - immunology; Virus Physiological Phenomena; bats; COVID-19; SARS-CoV-2; disease resistance; inflammation; inflammasome; immune complex; inflammatory diseases; longevity; viral reservoir
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2023.03.036

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. [Display omitted] •ASC2 is universally present and highly expressed in bats•Bat ASC2 is highly potent in dampening inflammasomes via ASC•Bat ASC2 attenuates sterile and virus-induced inflammation in mouse models•Mutation of 4 residues in human ASC2 allows it to gain bat-ASC2-like functionality Bats harbor many viruses and are long-lived. Bat ASC2, unlike its human counterpart, is a potent negative regulator of inflammasomes, thereby revealing a fundamentally distinct property of reduced inflammation in these animals in response to viruses and danger signals.