摘要
Inflammasomes and their product interleukin 18(IL-18)play important roles in gut microbiota monitoring and homeostasis,and their loss of function could lead to microbiota dysbiosis and accelerate disease progression.However,the impacts of the resulting microbiota dysbiosis on the mucosal immune system are largely unknown.Here,we show that dysbiotic microbiota from Il18^(-/-)mice induced immune cell loss in the small intestine(SI)in an inflammasome-independent manner.Cohousing experiments revealed that the immunotoxic phenotype of these microbiota was transferable to wild type(WT)mice and induced immune cell death through the receptor-interacting protein kinase 3(RIP3)-mixed lineage kinase domain like pseudokinase(MLKL)pathway.Analysis of microbiota composition identified two types of bacteria at the genus level,Ureaplasma and Parasutterella,that accumulated in Il18^(-/-)mice and negatively mediated changes in immune cells in the SI.Furthermore,dysbiosis in Il18^(-/-)mice also contributed to increased susceptibility to Listeria infection.Collectively,our results demonstrate that IL-18 is essential to microbiota homeostasis and that dysbiotic microbiota could significantly shape the landscape of the immune system.
炎症小体及其产物IL-18在肠道菌群监控和稳态维持方面发挥重要作用,其功能缺失会导致肠道菌群失衡并加速疾病进展,但其诱导的肠道菌群失衡对粘膜免疫系统的影响尚不清楚.本研究发现来自Il18^(-/-)小鼠的紊乱菌群以独立于炎症小体的方式诱导小肠免疫细胞的缺失.同窝喂养实验表明这些共生菌诱导小肠免疫细胞丢失的表型可转移至野生型(WT)小鼠,并通过RIP3-MLKL信号途径诱导免疫细胞死亡.共生菌组成分析在菌属水平上确定Ureaplasma和Parasutterella两类共生菌在Il18^(-/-)小鼠中富集并与小肠免疫细胞的丢失相关.此外,Il18^(-/-)小鼠的菌群失衡还导致其对李斯特菌的易感性增加.综上所述,本研究表明IL-18对共生菌的稳态至关重要且紊乱菌群可以显著地塑造免疫系统的格局.
作者
Xuesen Zheng
Lei Liu
Guangxun Meng
Shu Zhu
Rongbin Zhou
Wei Jiang
郑学森;刘蕾;孟广勋;朱书;周荣斌;江维(Hefei National Laboratory for Physical Sciences at Microscale,The CAS Key Laboratory of Innate Immunity and Chronic Disease,School of Basic Medical Sciences,Division of Life Sciences and Medicine,University of Science and Technology of China,Hefei 230027,China;The Center for Microbes,Development and Health,Key Laboratory of Molecular Virology and Immunology,Institut Pasteur of Shanghai,Chinese Academy of Sciences,Shanghai 200031,China;CAS Center for Excellence in Cell and Molecular Biology,University of Science and Technology of China,Hefei 230027,China)
基金
supported by the National Key Research and Development Program of China(2020YFA0509101)
the National Natural Science Foundation of China(91742202,81722022,and 81821001)
the Young Talent Support Program and Fundamental Research Funds for the Central Universities and the University Synergy Innovation Program of Anhui Province(GXXT-2019-026)。
