Department of Digestive Disease, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China.
Institute of Immunology and the Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic Disease, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China.
Proc Natl Acad Sci U S A. 2024 Feb 6;121(6):e2321419121. doi: 10.1073/pnas.2321419121. Epub 2024 Jan 30.
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-κB (NF-κB) 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 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 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.
NOD 样受体 (NLR) 家族包含pyrin 结构域的 6 (NLRP6) 作为肠道上皮细胞 (IECs) 中微生物双链 RNA 或脂磷壁酸 (LTA) 的传感器，启动包括炎性小体途径和 I 型干扰素 (IFN) 途径在内的多种途径，或调节核因子-κB (NF-κB) 和丝裂原活化蛋白激酶 (MAPK) 途径。NLRP6 可以以炎性小体依赖和非依赖的方式发挥其功能。然而，目前尚无工具可以区分单个 NLRP6 介导的途径对体内生理学和病理学的贡献。在这里，我们验证了小鼠 NLRP6 中 pyrin 结构域 (PYD) 的 Arg39 和 Trp50 残基对于 ASC 募集和炎性小体激活是必需的，但对于 RNA 结合和 PYD 非依赖性 NLRP6 寡聚化不重要。我们进一步生成了 突变小鼠，其在稳态肠道或病毒感染期间表现出炎性小体激活减少。然而，来自 突变小鼠的细胞或肠道组织中的 I 型 IFN 产生仍然正常。有趣的是，NLRP6 介导的炎性小体激活或 IFN-I 产生似乎在针对不同类型的 RNA 病毒的防御反应中发挥不同的作用。我们的工作生成了一种有用的工具，可用于研究 NLRP6 在体内的炎性小体依赖性作用，这可能有助于理解 NLRP6 介导的多条途径对肠道中复杂和动态环境线索的复杂性。
