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Background Paralytic ileus is common in patients with septic shock, which causes high morbidity and mortality. Enteric neurons and enteric glial cells (EGCs) regulate intestinal motility, but little is known about their interaction in endotoxemia. We aim to investigate whether reactive EGCs have harmful effects on enteric neurons and participate in intestinal motility disorder in mice during endotoxemia. Methods Endotoxemia was induced by lipopolysaccharide (LPS) intraperitoneal injection in mice. And fluorocitrate (FC) was administered before LPS injections to inhibit the reactive EGCs. The effects of reactive EGCs on intestinal motility were analyzed by motility assays in vivo and colonic migrating motor complexes (CMMCs) ex vivo. The number of enteric neurons was evaluated by immunofluorescent staining HuCD, nNOS and ChAT in vivo. In addition, we stimulated EGCs with IL-1β and TNF-α in vitro and cultured the primary enteric neurons in the conditioned medium, detecting the apoptosis and morphology of neurons through staining TUNEL, cleaved Caspase-3 protein and Anti-β-III tubulin. Results Intestinal motility and peristaltic reflex can be improved by the inhibition of reactive EGCs in vivo. There is an increased density of the neuronal population in the colonic myenteric plexus significantly while the reactive EGCs are inhibited, especially the nitrergic neurons. In vitro, the enteric neurons cultured in the conditioned medium of reactive EGCs had significantly more apoptotic rate and less dendritic complexity and number of primary neurites. Conclusion Reactive enteric glial cells participated in paralytic ileus by damaging nitrergic neurons during endotoxemia. It could provide a novel therapeutic strategy for intestinal motility disorders during endotoxemia or sepsis.

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Background The STING-TBK1-IRF3 signaling pathway involves in modulating host innate immunity, however, the potential role of STING signaling pathway in chronic restraint stress model has not been determined. The aim of this study is to explore the underlying role of STING signaling pathway in regulating neuroinflammation, as well as to evaluate the therapeutic potential of STING agonist during chronic restraint stress. Methods C57BL/6 mice were subjected to 14-day intermittent restraint stress. Sucrose preference, elevated plus maze and tail suspension tests were measured in chronic restraint stress mice. Expression levels of proinflammatory cytokines were tested by QT-PCR and Luminex cytokine assays. The fluorescence-labeled latex beads, flow cytometry and CD68 positive cell counts were utilized to evaluate phagocytic abilities of microglia. Then, the ability of intracerebroventricular injection of STING agonist, 2’3-cGAMP, to reverse the depression-like behaviors and inflammatory cytokines was examined. Results We found that the expression levels of STING, p-TBK1, and p-IRF3 were remarkably decreased in chronic restraint stress mice, which was associated with decreased IFN-β secretion. Moreover, the STING agonist, 2’3-cGAMP, significantly alleviated the neuroinflammation and ameliorated depression-like behavior which depends on the functional STING activation. Furthermore, 2’3-cGAMP promoted microglia phagocytosis through STING-dependent IFN-β release, which was essential for recovery from neuroinflammation during chronic restraint stress. Conclusions These findings demonstrate that STING signaling pathway is a critical mediator in regulating microglia phagocytosis and may serve as a novel therapeutic target for chronic stress-related psychiatric diseases.