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THU0070 A Nonpeptide AT2 Receptor Agonist Suppresses the Development of Collagen-Induced Arthritis by Upregulation of FoxP3+ Regulatory T Cells
  1. B. Sehnert1,2,
  2. G. Schett3,
  3. V. Valero-Esquitino4,
  4. R. Voll1,2,
  5. U. Steckelings4
  1. 1Department of Rheumatology and Clinical Immunology
  2. 2Center of Chronic Immunodeficiency, University Hospital Freiburg, Freiburg
  3. 3Department of Rheumatology and Clinical Immunology, University of Erlangen-Nürnberg, University Hospital Erlangen, Erlangen
  4. 4Center for Cardiovascular Research, Charité - Medical Faculty Berlin, Berlin, Germany

Abstract

Background Angiotensin II type 2 receptor (AT2R) signalling is not only related to inflammation, fibrosis, and end-organ damage but also exerts anti-inflammatory and anti-apoptotic actions [1]. Moreover, specific AT2R stimulation has neuroprotective features [2]. Compound 21 (C21) is the first non-peptide AT2 receptor agonist that stimulates selectively the AT2 receptor without affecting the AT1 receptor.

Objectives The objective of the present study was to investigate the therapeutic potential of C21 in collagen-induced arthritis (CIA) and to evaluate the role of Th1, Th17, and Treg subsets.

Methods Collagen-induced arthritis was induced according standard protocols [3], whereas C21 treatment was started at day 20 (0.1 mg/kg/day i.p.). The clinical severity was quantified according to a graded scale (0-4) for each paw and expressed as mean score of all four paws. For histological analysis the stained section (Hematoxylin/eosin, toluidine blue and tartrate-resistant acid phosphatase) were graded on a scale from 0-3. Serum Th1 cytokines and splenic FoxP3+ regulatory T cells of arthritic mice were analysed by flow cytometry. Quantitative RT-PCR analysis of sorted naive T-cells isolated from spleen and lymph nodes of C57BL/6 mice were performed to assess in vitro differentiation of Th0, Th1, Th17, and Treg cells in the presence of C21 (1µM).

Results Systemic treatment for 25 days with C21 ameliorated the clinical severity (p<0.05) of established CIA compared to the PBS group. The reduction on joint swelling using C21 was as effective as the application of Etanercept which we used as a positive control. The evaluation of the cumulative incidence presented that the clinic symptom onset was delayed in C21 treated mice. Histological scores of the hind paws showed lower numbers of inflammatory cells (p<0.01) and milder cartilage degradation (p<0.01), whereas no significant difference was detectable on bone destruction. The levels of destructive CII IgG2a did not deviate significantly between the groups. Furthermore, the number of CD4+Foxp3+ cells was significantly increased after C21 treatment (p<0.05) compared to the control group. This result is also reflected in our in vitro experiments. In vitro we detected decreased IFNγ mRNA expression in Th1, respectively a decrease in IL-17 mRNA expression in Th17 polarized T cells. In addition, C21 induced AT2R-stimulation resulted in a significant upregulation of FoxP3+ Treg cells in the presence of lineage-specific polarizing factors.

Conclusions C21 induced AT2R-stimulation attenuated severity and histological signs of established CIA. The observed anti-inflammatory effect of C21 might be a result of the expansion of CD4+ Treg cell numbers and the suppression of IL-17. C21 does not exhibit severe side-effects and therefore fulfil crucial prerequisites for an attractive concept in arthritis therapy.

References

  1. Steckelings, U.M., et al., The past, present and future of angiotensin II type 2 receptor stimulation. J Renin Angiotensin Aldosterone Syst, 2010. 11(1): p. 67-73.

  2. Namsolleck, P., et al., AT2-receptor stimulation enhances axonal plasticity after spinal cord injury by upregulating BDNF expression. Neurobiol Dis, 2012.

  3. Brand, D.D. et al., Collagen-induced arthritis. Nat Protoc, 2007. 2(5): p. 1269-75.

Disclosure of Interest None Declared

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