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* = Presenting author

P095 Immune compromised mice develop colitis upon denervation of the superior mesenteric nerve.

R. Willemze*1, L. Nijhuis1, O. Welting1, J. Folgering2, H. Darwinkel2, D. Chew3, A. Sridhar3, J. Witherington3, J. Seppen1, S. Heinsbroek1, W. de Jonge1

1Academic Medical Centre (AMC), Tytgat Institute for Liver and Intestinal Research, Amsterdam, Netherlands, 2Brains On-line B.V., Groningen, Netherlands, 3Glaxo Smith Kline, Bioelectronics, Middlesex, United Kingdom

Background

The autonomic nervous system plays a regulatory role in the immune response. It has been established in vitro that norepinephrine, one of the main sympathetic neurotransmitters, has anti-inflammatory effects on the myeloid compartment of the immune system.1 Our aim was to investigate the effect of mucosal norepinephrine depletion via chemical and surgical denervation in experimental colitis.

Methods

In a T-cell transfer colitis model, using Rag1-/- mice, chemical denervation was achieved using 6-hydroxydopamine (6-OHDA) or surgical denervation was accomplished by cutting the superior mesenteric nerve, a sympathetic nerve innervating the small intestine and colon. Colitis was evaluated after 14 days by histology, endoscopy, and mRNA levels of inflammatory cytokines, along with clinical parameters such as weight loss, colon weight, and diarrhoea. Intestinal norepinephrine was measured by mass spectrometry. Statistical significance between 2 groups was evaluated using a Mann–Whitney U test.

Results

Chemical as well as surgical denervation led to a significant decrease in intestinal norepinephrine (resp. p = 0.03 and p < 0.01). Chemical denervation had no effect on the course of T-cell transfer colitis. However, in mice that did not have a T-cell transfer, the colitis as assessed by histology score increased upon chemical denervation, almost reaching significance (p = 0.09). Interestingly, surgical denervation in wild-type mice had no effect, but in Rag1-/- mice without T-cell transfer, it caused significant weight loss (after 1 week p = 0.004) and increased colon weight (p < 0.01) and histology score (p < 0.01). Further, there was a significant increase of the pro-inflammatory cytokines IL-1β and IL-6 (both p < 0.01) in the colon after the surgical denervation in Rag1-/- mice reflecting spontaneous colitis.

Conclusion

In immune compromised mice, sympathetic denervation of the intestine leads to a decrease in intestinal norepinephrine, causing spontaneous colitis. These data are in line with earlier observed capacity of norepinephrine to induce tolerance in dendritic cells.1 Our data reveal a strong immune modulatory potential of the sympathetic nervous system.