Anti-inflammatory role of sympathetic nerves in chronic intestinal inflammation.
BACKGROUND
Substance P (SP) is a pro-inflammatory neuropeptide in colitis, whereas sympathetic neurotransmitters are anti-inflammatory at high concentrations.


OBJECTIVE
In all layers of the colon, nerve fibre densities of SP(+) and sympathetic nerve fibres were investigated (22 Crohn's disease, six diverticulitis, and 22 controls). In addition, the nerve fibre repellent factor semaphorin 3C (SEMA3C) was studied. The functional role of the sympathetic nervous system was tested in dextran sodium sulfate (DSS) and Il10(-/-) colitis.


RESULTS
In all layers, Crohn's disease patients demonstrated a loss of sympathetic nerve fibres. Sprouting of SP(+) nerve fibres was particularly observed in the mucosa and muscular layer in Crohn's disease. SEMA3C was detected in epithelial cells, and there was a marked increase of SEMA3C-positive crypts in the mucosa of Crohn's disease patients compared to controls. In Crohn's disease, the number of SEMA3C-positive crypts was negatively related to the density of mucosal sympathetic nerve fibres. Sympathectomy reduced acute DSS colitis but increased chronic DSS colitis. Sympathectomy also increased chronic colitis in Il10(-/-) mice.


CONCLUSIONS
This study demonstrated a loss of sympathetic and an increase of SP(+) nerve fibres in Crohn's disease. SEMA3C, a sympathetic nerve repellent factor, is highly expressed in the epithelium of Crohn's disease patients. In chronic experimental colitis, the sympathetic nervous system confers an anti-inflammatory influence. Thus, the loss of sympathetic nerve fibres in the chronic phase of the disease is most probably a pro-inflammatory signal, which might be related to repulsion of these fibres by SEMA3C and other repellents.
Straub
R H
RH
Laboratory of Neuroendocrino-Immunology, Department of Internal Medicine I, University Hospital Regensburg, 93042 Regensburg, Germany. rainer.straub@klinik.uni-regensburg.de
Grum
F
F
Strauch
U
U
Capellino
S
S
Bataille
F
F
Bleich
A
A
Falk
W
W
Schölmerich
J
J
Obermeier
F
F
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D003106:Colon / Q000294:innervation* / Q000378:metabolism / Q000473:pathology; D003424:Crohn Disease / Q000378:metabolism / Q000473:pathology*; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D004239:Diverticulitis, Colonic / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000172:deficiency; D008198:Lymph Nodes / Q000473:pathology; D008297:Male; D008643:Mesentery; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008875:Middle Aged; D009412:Nerve Fibers / Q000473:pathology; D013373:Substance P / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000473:pathology* / Q000503:physiopathology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D013373:Substance P; D007371:Interferon-gamma; D016264:Dextran Sulfate