Abstract
Abstract Background The maintenance and repair of the intestinal epithelial barrier (IEB) is a multifaceted process that requires the coordinated participation of different cell types within the gastrointestinal tract. Studies have shown that ablation of enteric glial cells (EGCs) can lead to intestinal epithelial cell necrosis and destruction of the IEB. However, the specific role of EGCs in it remains ambiguous. The aim of this study was to elucidate the potential role of EGCs in regulating IEB and intestinal inflammation. Methods In this study，we employed immunofluorescence, western blot, ELISA, and gene expression profiling to assess the expression of GFAP (a marker for EGCs), NGF, and necroptosis-associated proteins in intestinal tissues from IBD patients. In addition, DSS-induced colitis mouse models, in vitro co-culture systems, and transcriptomic analysis were used to explore the effects of EGCs and NGF on IECs necroptosis and inflammation. Results In intestinal tissues of IBD patients, reduced expression of GFAP and S100β suggests damage to EGCs. Additionally, we found that NGF in intestinal tissues primarily originates from EGCs. Diminished NGF secretion due to EGCs damage correlates with increased necroptosis of IECs. Exogenous administration of NGF inhibits DSS-induced necroptosis of IECs and alleviates colonic inflammation. Ablation of EGCs exacerbates necroptosis of IECs, disruption of IEB, and intestinal inflammation following DSS treatment. In vitro co-culture experiments demonstrate that EGCs suppress necroptosis of IECs induced by T/S/Z mix. Further flow cytometry and TEM results confirm that NGF effectively mitigates T/S/Z mix-induced necroptosis of IECs.Transcriptomic sequencing indicated that RNF126 is a downstream target in the NGF signaling pathway, potentially mediating the protective effects of EGCs-derived NGF on IECs. Conclusion Based on the findings from this study, it is evident that EGCs play a crucial role in maintaining intestinal homeostasis through their production of NGF. Reduced NGF secretion from damaged EGCs correlates with increased necroptosis of IECs, exacerbating inflammation in colonic tissues. Exogenous NGF administration effectively attenuates this process, highlighting its therapeutic potential in IBD. Furthermore, transcriptomic analysis identified RNF126 as a downstream mediator in the NGF signaling pathway, its specific role remains speculative and requires further investigation to elucidate its mechanistic involvement in mediating the protective effects of NGF. In conclusion, these findings emphasize the intricate interplay between EGCs, NGF signaling, and IEC survival, pointing towards novel therapeutic strategies targeting this pathway in IBD management.
Published Version
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