A mouse model to distinguish NLRP6-mediated inflammasome- dependent and- independent functions

• 成果类型: Article
• 署名作者: Li, Runzhi; Zan, Yang; Wang, Decai; Chen, Xuequn; Wang, Anmin; Tan, Haoyuan; Zhang, Guorong; Ding, Siyuan; Shen, Chen; Wu, Hao; Zhu, Shu
• 署名单位: Chinese Academy of Sciences; University of Science & Technology of China, CAS; Chinese Academy of Sciences; University of Science & Technology of China, CAS; Chinese Academy of Sciences; University of Science & Technology of China, CAS; Washington University (WUSTL); Washington University (WUSTL); Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Program in Cellular & Molecular Medicine (PCMM)
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9578
• DOI: 10.1073/pnas.2321419121
• 发表日期: 2024-01-29
• 关键词: rotavirus infection; innate immunity; nlrp6; receptors

摘要

The NOD - like receptor (NLR) family pyrin domain containing 6 (NLRP6) serves as a sensor for microbial dsRNA or lipoteichoic acid (LTA) in intestinal epithelial cells (IECs), and initiating multiple pathways including inflammasome pathway and type I interferon (IFN) pathway, or regulating nuclear factor-kappa B (NF-kappa B) and mitogen- activated protein kinase (MAPK) pathways. NLRP6 can exert its function in both inflammasome- dependent and inflammasome- independent manners. However, there is no tool to distinguish the contribution of individual NLRP6- mediated pathway to the physiology and pathology in vivo. Here, we validated that Arg39 and Trp50 residues in the pyrin domain (PYD) of murine NLRP6 are required for ASC recruitment and inflammasome activation, but are not important for the RNA binding and PYD- independent NLRP6 oligomerization. We further generated the Nlrp6R39E&W50E mutant mice, which showed reduced inflammasome activation in either steady state intestine or during viral infection. However, the type I IFN production in cells or intestine tissue from Nlrp6R39E&W50E mutant mice remain normal. Interestingly, NLRP6- mediated inflammasome activation or the IFN-I production seems to play distinct roles in the defense responses against different types of RNA viruses. Our work generated a useful tool to study the inflammasome- dependent role of NLRP6 in vivo, which might help to understand the complexity of multiple pathways mediated by NLRP6 in response to the complicated and dynamic environmental cues in the intestine.