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Role of the C5a receptor (C5aR) in acute and chronic dextran sulfate-induced models of inflammatory bowel disease

Authors

  • Kay Johswich PhD,

    1. Department of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany
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    • The first 2 authors contributed equally to the work.

  • Myriam Martin PhD,

    1. Department of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany
    Current affiliation:
    1. Department of Laboratory Medicine, University Hospital Malmö, Lund University; S-20502 Malmö, Sweden
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    • The first 2 authors contributed equally to the work.

  • Prof. André Bleich,

    1. Institute for Laboratory Animal Science and Central Animal Facility, Hannover Medical School, Hannover, Germany
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  • Prof. Michael Kracht,

    1. Rudolf-Buchheim-Institute of Pharmacology, Justus-Liebig-University, Giessen, Germany
    Current affiliation:
    1. Rudolf-Buchheim-Institute for Pharmacology, Justus-Liebig-University, D 35392 Giessen, Germany
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  • Oliver Dittrich-Breiholz,

    1. Institute for Biochemistry, Hannover Medical School, Hannover, Germany
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  • Prof. J. Engelbert Gessner,

    1. Clinical Immunology, Hannover Medical School, Hannover, Germany
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  • Prof. Sebastian Suerbaum,

    1. Department of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany
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  • Elisabeth Wende MD,

    1. Department of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany
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  • Prof. Claudia Rheinheimer,

    1. Department of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany
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  • Prof. Andreas Klos

    Corresponding author
    1. Department of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany
    • Department of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Carl-Neuberg-Strasse 1, D 30625 Hannover, Germany
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Abstract

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. (Inflamm Bowel Dis 2009;)

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