Regulation of intestinal immunity and tissue repair by enteric glia

摘要

Enteric glial cells have tissue-wide immunoregulatory roles through the upregulation of IFN gamma-dependent genes both at steady state and after parasite infection, promoting immune homeostasis and CXCL10-mediated tissue repair after pathogen-induced intestinal damage in mice.Tissue maintenance and repair depend on the integrated activity of multiple cell types(1). 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 (IFN gamma) gene signature. IFN gamma-dependent gene modules were also induced in EGCs from patients with inflammatory bowel disease(8). Single-cell transcriptomics analysis of the tunica muscularis showed that glia-specific abrogation of IFN gamma signalling leads to tissue-wide activation of pro-inflammatory transcriptional programs. Furthermore, disruption of the IFN gamma-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 IFN gamma signalling and provide evidence that this chemokine and the downstream amplification of IFN gamma signalling in the tunica muscularis are required for a measured inflammatory response to helminths and resolution of the granulomatous pathology. Our study demonstrates that IFN gamma signalling in enteric glia is central to intestinal homeostasis and reveals critical roles of the IFN gamma-EGC-CXCL10 axis in immune response and tissue repair after infectious challenge.