Role of the C5a receptor (C5aR) in acute and chronic dextran sulfate-induced models of inflammatory bowel disease.
BACKGROUND
Inflammatory bowel disease (IBD) is a critical public health issue; more and more people are affected, but treatment options remain limited. Complement activation and the anaphylatoxin C5a have been shown to play a role in IBD. In this study, mouse models of acute and chronic dextran sulfate-induced colitis were used to further elucidate the impact of C5a and its receptor (C5aR) on disease development.


METHODS
In C57BL/6J wildtype and C5aR(-/-) mice the extent of complement activation, changes in weight, and water/food consumption were determined. Disease severity was evaluated via a clinical score, histology, cytokine- and myeloperoxidase-determination as well as real-time reverse-transcriptase polymerase chain reaction (RT-PCR) for expression of anaphylatoxin receptors and inflammatory mediators.


RESULTS
C5aR(-/-) mice showed milder disease symptoms, less histological damage, and a lower expression of inflammatory mediators in acute colitis, a setting where complement was activated. In chronic colitis the knockout mice exhibited aggravated weight loss, a higher degree of histological damage and granulocyte infiltration. Intriguingly, increases in C3a-receptor and C5L2 mRNA were dependent on C5aR. Compared to wildtype mice, C5aR(-/-) animals displayed smaller lymph nodes in acute colitis, but extensive swelling and diminished IL-4 and IFN-γ responses in the chronic disease, demonstrating that C5aR modifies T-helper cell polarization.


CONCLUSIONS
C5aR exerts detrimental functions in acute colitis, strongly supporting the idea that a C5aR-antagonist might be useful for IBD treatment. However, since the absence of C5aR was no longer protective and in some regards disadvantageous in chronic IBD, future studies should address the efficacy and the possible side effects of a sustained antagonist treatment.
Johswich
Kay
K
Department of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany.
Martin
Myriam
M
Bleich
André
A
Kracht
Michael
M
Dittrich-Breiholz
Oliver
O
Gessner
J Engelbert
JE
Suerbaum
Sebastian
S
Wende
Elisabeth
E
Rheinheimer
Claudia
C
Klos
Andreas
A
D000208:Acute Disease; D000818:Animals; D016764:Cell Polarity / Q000276:immunology; D003167:Complement Activation / Q000276:immunology; D016264:Dextran Sulfate / Q000276:immunology / Q000633:toxicity; D015212:Inflammatory Bowel Diseases / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D007371:Interferon-gamma / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D044087:Receptor, Anaphylatoxin C5a / Q000235:genetics / Q000276:immunology*; D012720:Severity of Illness Index; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology
D044087:Receptor, Anaphylatoxin C5a; D015847:Interleukin-4; D007371:Interferon-gamma; D016264:Dextran Sulfate