Center for Immune-Related Diseases at Shanghai Institute of Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Immunology and Microbiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Front Immunol. 2024 Aug 26;15:1402834. doi: 10.3389/fimmu.2024.1402834. eCollection 2024.
Group 3 innate lymphoid cells (ILC3s) are enriched in the intestinal mucosa and play important roles in host defense against infection and inflammatory diseases. Sirtuin 6 (SIRT6) is a nicotinamide adenine dinucleotide (NAD+)- dependent deacetylase and has been shown to control intestinal epithelial cell differentiation and survival. However, the role of SIRT6 in ILC3s remains unknown.
To investigate the role of SIRT6 in gut ILC3s, we generated SIRT6 conditional knockout mice by crossing Rorccre and Sirt6flox/flox mice. Cell number and cytokine production was examined using flow cytometry. Citrobacter rodentium infection and dextran sodium sulfate-induced colitis models were used to determine the role of SIRT6 in gut defense. RT-qPCR, flow cytometry and immunohistochemistry were used to assess the intestinal inflammatory responses.
Here we show that SIRT6 inhibits IL-22 expression in intestinal ILC3s in a cell-intrinsic manner. Deletion of SIRT6 in ILC3s does not affect the cell numbers of total ILC3s and subsets, but results in increased IL-22 production. Furthermore, ablation of SIRT6 in ILC3s protects mice against Citrobacter rodentium infection and dextran sodium sulfate-induced colitis. Our results suggest that SIRT6 may play a role in ILC3 function by regulating gut immune responses against bacterial infection and inflammation.
Our finding provided insight into the relation of epigenetic regulators with IL-22 production and supplied a new perspective for a potential strategy against inflammatory bowel disease.
第三组固有淋巴细胞（ILC3）在肠道黏膜中丰富，并在宿主防御感染和炎症性疾病方面发挥重要作用。Sirtuin 6（SIRT6）是烟酰胺腺嘌呤二核苷酸（NAD+）依赖性去乙酰化酶，已被证明可控制肠道上皮细胞分化和存活。然而，SIRT6 在 ILC3 中的作用尚不清楚。
为了研究 SIRT6 在肠道 ILC3 中的作用，我们通过将 Rorccre 和 Sirt6flox/flox 小鼠杂交来生成 SIRT6 条件性敲除小鼠。使用流式细胞术检查细胞数量和细胞因子产生。使用柠檬酸杆菌感染和葡聚糖硫酸钠诱导的结肠炎模型来确定 SIRT6 在肠道防御中的作用。使用 RT-qPCR、流式细胞术和免疫组织化学来评估肠道炎症反应。
在这里，我们表明 SIRT6 以细胞内固有方式抑制肠道 ILC3 中的 IL-22 表达。在 ILC3 中缺失 SIRT6 不会影响总 ILC3 和亚群的细胞数量，但会导致 IL-22 产生增加。此外，在 ILC3 中缺失 SIRT6 可保护小鼠免受柠檬酸杆菌感染和葡聚糖硫酸钠诱导的结肠炎。我们的结果表明，SIRT6 可能通过调节针对细菌感染和炎症的肠道免疫反应在 ILC3 功能中发挥作用。
我们的发现提供了对表观遗传调节剂与 IL-22 产生之间关系的深入了解，并为针对炎症性肠病的潜在策略提供了新的视角。
