Nucleophosmin 1 Promotes Mucosal Immunity by Supporting Mitochondrial Oxidative Phosphorylation and ILC3 Activity. Nucleophosmin 1 Promotes Mucosal Immunity by Supporting Mitochondrial Oxidative Phosphorylation and ILC3 Activity

NPM1 is commonly mutated in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Concurrent inflammatory bowel diseases (IBD) and MDS have been reported frequently, indicating a close relationship between IBD and MDS. Here, we examined the role of NPM1 in IBD and colitis-associated colorectal cancer (CAC). NPM1 was reduced in IBD patients. Npm1+/- mice were more susceptible to acute colitis and experimentally induced CAC than littermate controls. Npm1 deficiency impaired the function of IL-22-producing group 3 innate lymphoid cells (ILC3s). Mice lacking Npm1 in ILC3s exhibited decreased IL-22 production and accelerated development of colitis. NPM1 was important for mitochondrial biogenesis and metabolism by oxidative phosphorylation in ILC3s. Further experiments revealed that NPM1 cooperates with p65 to promote TFAM transcription in ILC3s. Overexpression of Npm1 in mice enhanced ILC3 function and reduced severity of DSS-induced colitis. Thus, our findings suggest the protective function of NPM1 in ILC3s against IBD by regulating mitochondrial metabolism through p65-TFAM axis. Overall design: To uncover mechanisms by which NPM1 regulates ILC3 expansion and function, we performed RNA sequencing (smart-seq2) of Live+Lin-CD45lowCD90high LPLs from colon of WT and Npm1+/- mice with colitis induced by DSS treatment.

核仁磷酸蛋白1（NPM1）常见于骨髓增生异常综合征（myelodysplastic syndrome, MDS）与急性髓系白血病（acute myeloid leukemia, AML）中发生突变。既往已有大量研究报道炎症性肠病（inflammatory bowel diseases, IBD）与MDS可合并存在，提示二者间存在密切关联。本研究探讨了NPM1在IBD及结肠炎相关结直肠癌（colitis-associated colorectal cancer, CAC）中的作用。

研究发现，IBD患者体内NPM1的表达水平显著降低。与同窝野生型（wild type, WT）对照小鼠相比，Npm1+/-小鼠更易罹患急性结肠炎及实验诱导型CAC。Npm1缺陷会损伤分泌白细胞介素22（interleukin 22, IL-22）的3型天然淋巴细胞（ILC3s）的功能。特异性敲除ILC3s中Npm1的小鼠，其IL-22产生量减少且结肠炎发病进程加速。NPM1对ILC3s的线粒体生物发生及氧化磷酸化介导的代谢过程至关重要。进一步实验显示，NPM1可与p65协同，促进ILC3s中线粒体转录因子A（TFAM）的转录。在小鼠体内过表达Npm1可增强ILC3s功能，减轻葡聚糖硫酸钠（dextran sulfate sodium, DSS）诱导的结肠炎严重程度。

综上，本研究结果表明，NPM1可通过p65-TFAM轴调控ILC3s的线粒体代谢，从而在IBD中发挥保护性作用。

本研究的总体实验设计：为阐明NPM1调控ILC3s扩增与功能的分子机制，我们对经DSS诱导结肠炎的野生型与Npm1+/-小鼠的结肠组织中分离得到的活细胞阳性、谱系标记阴性的CD45低表达CD90高表达肠黏膜固有层淋巴细胞（Live+Lin-CD45lowCD90high LPLs）进行了RNA测序（smart-seq2）。