Bhattarai Bishan, Antonova Alina Ulezko, Fachi Jose L, Hopkins Leone S, McCullen Matthew V D, Saini Ankita, Oliveira Sarah de, Beatty Wandy L, Musiek Erik S, Kuchroo Vijay K, Lazar Mitchell A, Oltz Eugene M, Colonna Marco
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, USA.
Nat Immunol. 2025 Aug 13. doi: 10.1038/s41590-025-02240-5.
The gut experiences daily fluctuations in microbes and nutrients aligned with circadian rhythms that regulate nutrient absorption and immune function. Group 3 innate lymphoid cells (ILC3s) support gut homeostasis through interleukin-22 (IL-22) but can convert into interferon-γ-producing ILC1s. How circadian proteins control this plasticity remains unclear. Here we showed that the circadian proteins REV-ERBα and REV-ERBβ maintain ILC3 identity. Their combined deletion promoted ILC3-to-ILC1 conversion, reduced energy metabolism and IL-22 production, increased interferon-γ production, and heightened susceptibility to Citrobacter rodentium infection. Single-cell multiomics and gene editing revealed that REV-ERBα/REV-ERBβ deficiency upregulated the transcription factor NFIL3, which repressed the expression of RORγt via a -2-kb cis-regulatory element in the Rorc gene, shifting cells toward a T-bet-driven state. Chromatin and metabolic analyses indicated that REV-ERBα/REV-ERBβ loss reprogrammed regulatory and metabolic circuits. Thus, REV-ERBα/REV-ERBβ safeguard gut integrity by regulating clock genes that control RORγt expression and preserve ILC3 identity and resistance to intestinal inflammation.
肠道内的微生物和营养物质每天都会随着昼夜节律发生波动，而昼夜节律会调节营养物质的吸收和免疫功能。3型天然淋巴细胞（ILC3s）通过白细胞介素-22（IL-22）维持肠道内环境稳定，但可转化为产生干扰素-γ的ILC1s。昼夜节律蛋白如何控制这种可塑性尚不清楚。在这里，我们表明昼夜节律蛋白REV-ERBα和REV-ERBβ维持ILC3的特性。它们的联合缺失促进了ILC3向ILC1的转化，降低了能量代谢和IL-22的产生，增加了干扰素-γ的产生，并增强了对鼠柠檬酸杆菌感染的易感性。单细胞多组学和基因编辑显示，REV-ERBα/REV-ERBβ缺陷上调了转录因子NFIL3，该因子通过Rorc基因中一个-2-kb的顺式调节元件抑制RORγt的表达，使细胞向T-bet驱动的状态转变。染色质和代谢分析表明，REV-ERBα/REV-ERBβ的缺失重新编程了调节和代谢回路。因此，REV-ERBα/REV-ERBβ通过调节控制RORγt表达的时钟基因来保护肠道完整性，并维持ILC3的特性和对肠道炎症的抵抗力。
