Session Information
Session Type: Abstract Submissions (ACR)
Background/Purpose:
The renin-angiotensin system (RAS) is known to play an important role in inflammation, fibrosis, and end-organ damage. Moreover, AT2R signalling exerts anti-inflammatory and anti-apoptotic actions. Specific AT2R stimulation exhibits also neuroprotective characteristics. Compound 21 (C21) is the first non-peptide AT2 receptor agonist that stimulates selectively the AT2 receptor without affecting the AT1 receptor.
In the present study we examine the therapeutic potential of C21 in collagen-induced arthritis (CIA) and assess the role of Th1, Th17, and Treg subsets.
Methods: Collagen-induced arthritis was induced according standard protocols. Daily C21 treatment (0.1 mg/kg/i.p.) was started at day 20 after immunization. Etanercept was used as positive control. Disease activity was assessed by clinical scoring to a graded scale (0-4). At day 48 hind paws were removed for histological analysis. The stained sections (Hematoxylin/eosin, toluidine blue and tartrate-resistant acid phosphatase) were graded on a scale from 0-3. Serum cytokine profile (Th1) and splenic FoxP3+ regulatory T cells of arthritic mice were analysed by flow cytometry. In vitro differentiation of Th0, Th1, Th17, and Treg cells in the presence of C21 (1µM) was investigated using quantitative RT-PCR analysis of sorted naive T-cells isolated from spleen and lymph nodes of C57BL/6 mice.
Results: Systemic treatment with C21 attenuated the clinical severity of established CIA compared to the PBS group (p<0.005). The therapeutic efficacy of C21 was comparable to Etanercept which we used as a positive control. C21 administration reduced the cumulative incidence in CIA. Histological evaluation of C21 sections showed a well preserved articular cartilage and minor inflammatory infiltrates correlating with a reduction in disease severity. No significant difference between the groups was detectable on bone destruction. C21 did not suppress CIA by inhibition of anti-CII antibody production. Furthermore, the number of CD4+Foxp3+ cells was significantly increased after in vivo C21 treatment (p<0.05) compared to the PBS group. In vitro we detected decreased IFNγ mRNA expression in Th1, respectively a decrease in IL-17 mRNA expression in Th17 polarized T cells. Moreover, in vitro treatment of naïve T-cells with C21 significantly upregulated FoxP3+Treg cells in the presence of polarizing factors.
Conclusion: C21-mediated AT2R-stimulation suppresses clinical severity, incidence and histological signs of established CIA. The regulation of IL-17-producing Th17 cells towards regulatory T cells (Treg) might explain the observed anti-inflammatory effect. Due to the absence of severe side-effects, C21 treatment presents an attractive concept in arthritis therapy.
Disclosure:
B. Sehnert,
None;
V. Valero-Esquitino,
None;
G. Schett,
None;
U. M. Steckelings,
None;
R. E. Voll,
None.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/specific-angiotensin-type-ii-receptor-stimulation-attenuates-collagen-induced-arthritis-via-enhancement-of-foxp3-regulatory-t-cells/