Tissue maintenance and repair depend on the integrated activity of multiple cell types¹. Whereas the contributions of epithelial^2,3, immune^4,5 and stromal cells^6,7 in intestinal tissue integrity are well understood, the role of intrinsic neuroglia networks remains largely unknown. Here we uncover important roles of enteric glial cells (EGCs) in intestinal homeostasis, immunity and tissue repair. We demonstrate that infection of mice with Heligmosomoides polygyrus leads to enteric gliosis and the upregulation of an interferon gamma (IFNγ) gene signature. IFNγ-dependent gene modules were also induced in EGCs from patients with inflammatory bowel disease⁸. Single-cell transcriptomics analysis of the tunica muscularis showed that glia-specific abrogation of IFNγ signalling leads to tissue-wide activation of pro-inflammatory transcriptional programs. Furthermore, disruption of the IFNγ–EGC signalling axis enhanced the inflammatory and granulomatous response of the tunica muscularis to helminths. Mechanistically, we show that the upregulation of Cxcl10 is an early immediate response of EGCs to IFNγ signalling and provide evidence that this chemokine and the downstream amplification of IFNγ signalling in the tunica muscularis are required for a measured inflammatory response to helminths and resolution of the granulomatous pathology. Our study demonstrates that IFNγ signalling in enteric glia is central to intestinal homeostasis and reveals critical roles of the IFNγ–EGC–CXCL10 axis in immune response and tissue repair after infectious challenge.

组织维护和修复取决于多种细胞类型¹的综合活动。尽管上皮细胞^2,3、免疫细胞^4,5和基质细胞^6,7在肠组织完整性中的作用已广为人知，但内在神经胶质网络的作用仍然很大程度上未知。在这里，我们揭示了肠神经胶质细胞 (EGC) 在肠道稳态、免疫和组织修复中的重要作用。我们证明用Heligmosomoides polygyrus感染小鼠会导致肠神经胶质增生和干扰素 γ (IFNγ) 基因特征的上调。炎症性肠病患者的 EGC 中也诱导了 IFNγ 依赖性基因模块⁸. 肌层的单细胞转录组学分析表明，神经胶质细胞特异性消除 IFNγ 信号传导导致全组织激活促炎转录程序。此外，干扰素γ-EGC信号轴的破坏增强了肌层对蠕虫的炎症和肉芽肿反应。从机制上讲，我们表明Cxcl10的上调是EGCs对IFNγ信号的早期即时反应，并提供证据表明这种趋化因子和肌层中IFNγ信号的下游放大是测量对蠕虫的炎症反应和解决肉芽肿病理学所必需的。我们的研究表明，肠神经胶质细胞中的 IFNγ 信号传导是肠道稳态的核心，并揭示了 IFNγ-EGC-CXCL10 轴在感染性攻击后免疫反应和组织修复中的关键作用。