Group 3 innate lymphoid cells(ILC3s)play critical roles in innate immunity and gut homeostasis.However,how ILC3 homeostasis is regulated remains elusive.Here,we identified a novel circular RNA,circZbtb20,that is highl...Group 3 innate lymphoid cells(ILC3s)play critical roles in innate immunity and gut homeostasis.However,how ILC3 homeostasis is regulated remains elusive.Here,we identified a novel circular RNA,circZbtb20,that is highly expressed in ILC3s and required for their maintenance and function.CircZbtb20 deletion causes reduced ILC3 numbers,increasing susceptibility to C.rodentium infection.Mechanistically,circZbtb20 enhances the interaction of Alkbh5 with Nr4a1 mRNA,leading to ablation of the m6A modification of Nr4a1 mRNA to promote its stability.Nr4a1 initiates Notch2 signaling activation,which contributes to the maintenance of ILC3 homeostasis.Deletion of Alkbh5 or Nr4a1 also impairs ILC3 homeostasis and increases susceptibilities to bacterial infection.Thus,our findings reveal an important role of circular RNA in the regulation of innate lymphoid cell homeostasis.展开更多
Objective To explore the role of MyD88 signaling in MHV-3 virus-mediated fulminant hepatitis. Methods We evaluated liver lesion status, the expression of multiple pro-inflammatory cytokines and HMGB1, the recruitment ...Objective To explore the role of MyD88 signaling in MHV-3 virus-mediated fulminant hepatitis. Methods We evaluated liver lesion status, the expression of multiple pro-inflammatory cytokines and HMGB1, the recruitment of inflammatory ILC3, and mortality in MyD88-/-and WT mice. Results The expression of multiple pro-inflammatory cytokines that recruit inflammatory ILC3 to the liver was severely impaired in MyD88-/-mice resulting in reduced liver pathology, viral replication, and mortality post-infection. Additionally, MHV-3 markedly increased the expression of high-mobility group box 1(HMGB1) in infected hepatocytes/macrophages and induced HMGB1 protein migration from the nucleus to the extracellular milieu, where it activates MyD88-dependent inflammation. Conclusion Our findings indicate that MyD88 exacerbates immunological pathology in experimental viral fulminant hepatitis.展开更多
基金supported by the Ministry of Science and Technology of China(2020YFA0803501 and 2019YFA0508501)the National Natural Science Foundation of China⑶930036,81921003,92042302,31870883,91940305,31728006,81772646,and 31871494)+3 种基金the Strategic Priority Research Programs of the Chinese Academy of Sciences(XDB19030203)the Beijing Natural Science Foundation(5192018)the Biological Resource Program of the Chinese Academy of Science(KFJ-BRP-017-04)the Young Elite Scientist Sponsorship Program of CAST(2018QNRC001).
文摘Group 3 innate lymphoid cells(ILC3s)play critical roles in innate immunity and gut homeostasis.However,how ILC3 homeostasis is regulated remains elusive.Here,we identified a novel circular RNA,circZbtb20,that is highly expressed in ILC3s and required for their maintenance and function.CircZbtb20 deletion causes reduced ILC3 numbers,increasing susceptibility to C.rodentium infection.Mechanistically,circZbtb20 enhances the interaction of Alkbh5 with Nr4a1 mRNA,leading to ablation of the m6A modification of Nr4a1 mRNA to promote its stability.Nr4a1 initiates Notch2 signaling activation,which contributes to the maintenance of ILC3 homeostasis.Deletion of Alkbh5 or Nr4a1 also impairs ILC3 homeostasis and increases susceptibilities to bacterial infection.Thus,our findings reveal an important role of circular RNA in the regulation of innate lymphoid cell homeostasis.
基金Supported by grants from the National Natural Sciences Foundation of China(No.81361120400 and 81222023)
文摘Objective To explore the role of MyD88 signaling in MHV-3 virus-mediated fulminant hepatitis. Methods We evaluated liver lesion status, the expression of multiple pro-inflammatory cytokines and HMGB1, the recruitment of inflammatory ILC3, and mortality in MyD88-/-and WT mice. Results The expression of multiple pro-inflammatory cytokines that recruit inflammatory ILC3 to the liver was severely impaired in MyD88-/-mice resulting in reduced liver pathology, viral replication, and mortality post-infection. Additionally, MHV-3 markedly increased the expression of high-mobility group box 1(HMGB1) in infected hepatocytes/macrophages and induced HMGB1 protein migration from the nucleus to the extracellular milieu, where it activates MyD88-dependent inflammation. Conclusion Our findings indicate that MyD88 exacerbates immunological pathology in experimental viral fulminant hepatitis.
文摘目的·探究雷帕霉素靶蛋白复合物1(mechanistic target of rapamycin complex 1,mTORC1)对3型固有淋巴细胞(group 3 innate lymphoid cell,ILC3)功能的影响。方法·使用mTORC1信号通路的特异性抑制剂雷帕霉素体外刺激野生型C57BL/6小鼠肠道固有层淋巴细胞(lamina propria leukocyte,LPL),初步观察ILC3细胞数量及功能的变化;之后采用流式细胞技术分选出小鼠肠道ILC3,用白细胞介素23(interleukin 23,IL-23)刺激使其活化,再通过实时荧光定量PCR检测活化后ILC3中编码转录因子视黄酸受体相关的孤儿核受体(retinoic acid receptor related orphan receptor,RORγt)、IL-22及mTORC1关键组分Raptor(regulatory associated protein of mTOR)的基因mRNA水平;构建ILC3细胞特异性敲除Raptor的基因工程小鼠,使用苏木精-伊红染色、流式细胞技术和实时荧光定量PCR检测mTORC1功能缺失后对肠道结构、结肠ILC3细胞数量及功能的影响。结果·雷帕霉素刺激后LPL中ILC3数量无变化,但分泌IL-22减少;ILC3被IL-23激活后,检测到编码Raptor、RORγt和IL-22的基因mRNA表达水平同步上调;Raptor缺失的小鼠肠道结构无明显损伤,结肠ILC3数量和亚群比例与对照小鼠无明显差异,但ILC3活化后分泌细胞因子IL-22的水平显著下降。结论·mTORC1功能缺失显著抑制ILC3分泌IL-22的能力,对肠道结构及肠道ILC3的发育无影响,可见mTORC1信号对肠道ILC3功能具有正向调控作用。
