Project description:Tissue maintenance and repair depend on the integrated activity of multiple cell types. Whereas the contributions of epithelial, immune and stromal cells in intestinal tissue integrity are well understood, the role of intrinsic neuroglia networks remains largely unknown. Here, we uncover pivotal roles of enteric glial cells (EGCs) in intestinal homeostasis, immunity and tissue repair. We demonstrate that infection of mice with Heligmosomoides polygyrus (H. poly) leads to enteric gliosis and upregulation of the interferon gamma (IFN-γ) gene signature. Single-cell transcriptomics of tunica muscularis (TM) showed that glia-specific abrogation of IFN-γ signaling leads to tissue-wide activation of pro-inflammatory transcriptional programs. In addition, disruption of the IFN-γ-EGC signaling axis enhanced the inflammatory and granulomatous response of TM to helminths. Mechanistically, we show that upregulation of Cxcl10 is an early immediate response of EGCs to IFN-γ signaling and provide evidence that this chemokine and the downstream amplification of IFN-γ signaling in the TM are required for a measured inflammatory response to helminths and resolution of granulomatous pathology. Our study demonstrates that IFN-γ signaling in enteric glia is central to intestinal homeostasis and reveals critical roles of the IFN-γ-EGC-Cxcl10 axis in immune response and tissue repair following infectious challenge. To characterize the response of enteric glia to helminth infection at single cell resolution, we next performed scRNAseq (C1 Fluidigm platform) of tdT+ cells from the TM of naïve and H. poly-infected mice.
Project description:Tissue maintenance and repair depend on the integrated activity of multiple cell types. Whereas the contributions of epithelial, immune and stromal cells in intestinal tissue integrity are well understood, the role of intrinsic neuroglia networks remains largely unknown. Here, we uncover pivotal roles of enteric glial cells (EGCs) in intestinal homeostasis, immunity and tissue repair. We demonstrate that infection of mice with Heligmosomoides polygyrus (H. poly) leads to enteric gliosis and upregulation of the interferon gamma (IFN-γ) gene signature. Single-cell transcriptomics of tunica muscularis (TM) showed that glia-specific abrogation of IFN-γ signaling leads to tissue-wide activation of pro-inflammatory transcriptional programs. In addition, disruption of the IFN-γ-EGC signaling axis enhanced the inflammatory and granulomatous response of TM to helminths. Mechanistically, we show that upregulation of Cxcl10 is an early immediate response of EGCs to IFN-γ signaling and provide evidence that this chemokine and the downstream amplification of IFN-γ signaling in the TM are required for a measured inflammatory response to helminths and resolution of granulomatous pathology. Our study demonstrates that IFN-γ signaling in enteric glia is central to intestinal homeostasis and reveals critical roles of the IFN-γ-EGC-Cxcl10 axis in immune response and tissue repair following infectious challenge. To characterize the response of enteric glia to helminth infection, we performed bulk RNAseq of tdT+ cells (=EGCs) and tdT- cells (=non-glia cells) from the TM of naïve and H. poly-infected Sox10CreERT2;Rosa26tdTomato mice.
Project description:Tissue maintenance and repair depend on the integrated activity of multiple cell types. Whereas the contributions of epithelial, immune and stromal cells in intestinal tissue integrity are well understood, the role of intrinsic neuroglia networks remains largely unknown. Here, we uncover pivotal roles of enteric glial cells (EGCs) in intestinal homeostasis, immunity and tissue repair. We demonstrate that infection of mice with Heligmosomoides polygyrus (H. poly) leads to enteric gliosis and upregulation of the interferon gamma (IFN-γ) gene signature. Single-cell transcriptomics of tunica muscularis (TM) showed that glia-specific abrogation of IFN-γ signaling leads to tissue-wide activation of pro-inflammatory transcriptional programs. In addition, disruption of the IFN-γ-EGC signaling axis enhanced the inflammatory and granulomatous response of TM to helminths. Mechanistically, we show that upregulation of Cxcl10 is an early immediate response of EGCs to IFN-γ signaling and provide evidence that this chemokine and the downstream amplification of IFN-γ signaling in the TM are required for a measured inflammatory response to helminths and resolution of granulomatous pathology. Our study demonstrates that IFN-γ signaling in enteric glia is central to intestinal homeostasis and reveals critical roles of the IFN-γ-EGC-Cxcl10 axis in immune response and tissue repair following infectious challenge. To understand mechanistically how the IFN-γ-EGC axis regulates the intestinal response to helminth infection, we used scRNAseq analysis of the TM as an unbiased means to identify tissue-wide changes in cellular composition and gene expression associated with glia-specific abrogation of IFN-γ signalling.
