Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
Cell. 2020 Jan 9;180(1):50-63.e12. doi: 10.1016/j.cell.2019.12.016.
Mucosal barrier immunity is essential for the maintenance of the commensal microflora and combating invasive bacterial infection. Although immune and epithelial cells are thought to be the canonical orchestrators of this complex equilibrium, here, we show that the enteric nervous system (ENS) plays an essential and non-redundant role in governing the antimicrobial protein (AMP) response. Using confocal microscopy and single-molecule fluorescence in situ mRNA hybridization (smFISH) studies, we observed that intestinal neurons produce the pleiotropic cytokine IL-18. Strikingly, deletion of IL-18 from the enteric neurons alone, but not immune or epithelial cells, rendered mice susceptible to invasive Salmonella typhimurium (S.t.) infection. Mechanistically, unbiased RNA sequencing and single-cell sequencing revealed that enteric neuronal IL-18 is specifically required for homeostatic goblet cell AMP production. Together, we show that neuron-derived IL-18 signaling controls tissue-wide intestinal immunity and has profound consequences on the mucosal barrier and invasive bacterial killing.
黏膜屏障免疫对于维持共生菌群和抵御侵袭性细菌感染至关重要。尽管免疫细胞和上皮细胞被认为是这种复杂平衡的典型协调者，但在这里，我们表明肠神经系统（ENS）在调节抗菌蛋白（AMP）反应方面发挥着必不可少且不可或缺的作用。通过共聚焦显微镜和单分子荧光原位 mRNA 杂交（smFISH）研究，我们观察到肠道神经元产生多效细胞因子 IL-18。引人注目的是，仅从肠神经元中删除 IL-18，而不是免疫细胞或上皮细胞，会使小鼠易感染侵袭性鼠伤寒沙门氏菌（S.t.）感染。从机制上讲，无偏 RNA 测序和单细胞测序表明，肠神经元中的 IL-18 特异性地需要用于稳态杯状细胞 AMP 的产生。总之，我们表明，神经元衍生的 IL-18 信号控制着肠道的广泛免疫，并对黏膜屏障和侵袭性细菌杀伤产生深远影响。
