Blockage of the neurokinin 1 receptor and capsaicin-induced ablation of the enteric afferent nerves protect SCID mice against T-cell-induced chronic colitis.

Abstract

BACKGROUND:

The neurotransmitter substance P (SP) released by, and the transient receptor potential vanilloid (TRPV1), expressed by afferent nerves, have been implicated in mucosal neuro-immune-regulation. To test if enteric afferent nerves are of importance for the development of chronic colitis, we examined antagonists for the high-affinity neurokinin 1 (NK-1) SP receptor and the TRPV1 receptor agonist capsaicin in a T-cell transfer model for chronic colitis.

METHODS:

Chronic colitis was induced in SCID mice by injection of CD4(+)CD25(-) T cells. The importance of NK-1 signaling and TRPV1 expressing afferent nerves for disease development was studied in recipient SCID mice systemically treated with either high-affinity NK-1 receptor antagonists or neurotoxic doses of capsaicin. In addition, we studied the colitis-inducing effect of NK-1 receptor deleted CD4(+)CD25(-) T cells.

RESULTS:

Treatment with the NK-1 receptor antagonist CAM 4092 reduced the severity of colitis, but colitis was induced by NK-1 receptor-deleted T cells, suggesting that SP in colitis targets the recipient mouse cells and not the colitogenic donor T cells. Capsaicin-induced depletion of nociceptive afferent nerves prior to CD4(+)CD25(-) T-cell transfer completely inhibited the development of colitis.

CONCLUSIONS:

Our data demonstrate the importance of an intact enteric afferent nerve system and NK-1 signaling in mucosal inflammation and may suggest new treatment modalities for patients suffering from inflammatory bowel disease.

• Authors: Monika Gad, Anders Elm Pedersen, Nanna Ny Kristensen, Carmen de Felipe Fernandez, Mogens H Claesson
• Journal: Inflammatory bowel diseases (Inflamm Bowel Dis) Vol. 15 Issue 8 Pg. 1174-82 (Aug 2009) ISSN: 1536-4844 [Electronic] England
• PMID: 19326358 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• Homeodomain Proteins
• Interleukin-2 Receptor alpha Subunit
• Neurokinin-1 Receptor Antagonists
• Receptors, Neurokinin-1
• Sensory System Agents
• TRPV Cation Channels
• TRPV1 receptor
• RAG-1 protein
• Capsaicin

Topics

• Animals
• CD4-Positive T-Lymphocytes (metabolism)
• Capsaicin (pharmacology)
• Chronic Disease
• Colitis (chemically induced, immunology, prevention & control)
• Cytokines (metabolism)
• Enteric Nervous System (drug effects, metabolism)
• Female
• Flow Cytometry
• Homeodomain Proteins (physiology)
• Humans
• Interleukin-2 Receptor alpha Subunit (metabolism)
• Intestinal Mucosa (innervation)
• Mice
• Mice, Inbred BALB C
• Mice, Knockout
• Mice, SCID
• Neurokinin-1 Receptor Antagonists
• Neurons, Afferent (drug effects, metabolism)
• Receptors, Neurokinin-1 (physiology)
• Sensory System Agents (pharmacology)
• T-Lymphocytes (immunology)
• TRPV Cation Channels (metabolism)