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P015 Interaction between enteric glia and myeloid cells as critical players in intestinal immune homeostasis.

G. Goverse*, M. Stakenborg, M. van Winge, E. Labeeuw, G. Farro, M. Hao, P. J. Gomez Pinilla, G. Boeckxstaens, G. Matteoli

KU Leuven, P.O. Box 701, Department of Clinical and Experimental Medicine, Leuven, Belgium

Background

In the gastrointestinal tract balance between immune activation and tolerance is essential to maintain intestinal homoeostasis. We have demonstrated that activation of the enteric nervous system (ENS) has potent anti-inflammatory effect on macrophages (MFs) and dendritic cells (DCs) via the release of acetylcholine. In the current study, we aim to investigate if also enteric glial cells (EGCs), the mayor cellular constituent of the ENS, may have modulatory effects directly on intestinal immune cells and play a role in preserving intestinal immune homeostasis.

Methods

Immune labelling with specific antibodies was performed to study the interaction between EGCs and intestinal immune cells within the muscularis externa and in the lamina propria. To study the possible anti-inflammatory effect of EGC-released factors, EGCs were isolated from the muscularis externa of wild-type mice and cultured with bone marrow–derived MFs or DCs. After co-culture with EGCs or with the glia-derived neurotrophic factor (GDNF), the phenotype of MFs and DCs was analysed by gene expression. In some experiments, to analyse the participation of enteric glia in vivo during intestinal inflammation, EGCs were FACS sorted from control or mice exposed to 5 days of dextran sodium sulphate (DSS), and gene expression was analysed.

Results

Anatomical analysis with confocal microscopy revealed that EGCs are in close contact with intestinal immune cells such as MFs and DCs both in the muscularis externa and in the lamina propria. Interestingly, glial-secreted molecules were able to decrease expression of pro-inflammatory cytokine IL-12 in both MFs and DCs after LPS stimulation, whereas anti-inflammatory cytokine IL-10 was increased. In addition, typical M2 anti-inflammatory markers such as MRC-1, Lyve-1 and Stab-1 were increased in MFs stimulated with EGC supernatant or GDNF. In vivo after DSS treatment, EGCs express high level of CX3CR1L, a chemokine that typically attracts CX3CR1+ monocytes and genes involved in the synthesis of the tolerogenic molecule retinoic acid (ie, RALDH3).

Conclusion

We provide anatomical, in-vitro, and in-vivo evidences suggesting that EGCs exert immunomodulatory effects on intestinal antigen presenting cells. We are currently testing the hypothesis that during inflammation the enteric glia would be able to attract and influence monocytes inducing a tolerogenic phenotype in these cells. Taken together, our data indicate that interaction between enteric glia and the intestinal immune system might be crucial to maintain intestinal immune homeostasis and prevent intestinal immune-­mediated diseases such as IBD.