Activation Of Liver X Receptors Inhibits Experimental Fibrosis By Interfering With Interleukin-6 Release From Macrophages

Christian Beyer¹, Jürgen Beer¹, Katrin Palumbo-Zerr¹, Pawel Zerr¹, Alfiya Distler¹, Clara Dees¹, Louis E. Munoz¹, Gerhard Krönke¹, Oliver Distler², Steve Anderson³, Georg A. Schett⁴ and Joerg H. W. Distler¹, ¹Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany, ²Department of Rheumatology and Center of Experimental Rheumatology, University Hospital Zurich, Zurich, Switzerland, ³Lexicon Pharmaceuticals Inc., The Woodlands, TX, ⁴Dept of Medicine 3, Rheumatology and Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: Fibroblasts, interleukins (IL), Macrophage, nuclear hormone receptor and systemic sclerosis

Session Information

Title: Systemic Sclerosis, Fibrosing Syndromes and Raynaud’s-Pathogenesis, Animal Models and Genetics I: Therapeutic Interventions in Preclinical Animal Models of Scleroderma

Session Type: Abstract Submissions (ACR)

Background/Purpose: Liver X receptors (LXRs) are orphan nuclear receptors with emerging roles in metabolic and autoimmune diseases. Here, we investigated the role of LXRs in experimental skin fibrosis and evaluated their potential as anti-fibrotic targets for systemic sclerosis (SSc) and other fibrotic diseases.

Methods: We studied the role of LXRs in bleomycin-induced skin fibrosis and in tight skin-1 (Tsk-1) mice, reflecting different subtypes of fibrotic disease. To dissect the role of both LXR isoforms in fibrosis, we generated LXRα- and LXRβ-knockout mice as well as LXR-α/β-double-knockout mice. To establish the mode of action of the anti-fibrotic effects of LXRs, we investigated the effects of LXRs on fibroblasts and macrophages.

Results: LXR activation by the LXR agonist T0901317 had potent anti-fibrotic effects in both bleomycin-induced skin fibrosis and Tsk-1 mice as assessed by skin thickness, hydroxyproline content, and the number of myofibroblasts. The anti-fibrotic activity of LXRs was particularly prominent in the inflammatory bleomycin-model in which LXR activation reduced skin thickening by up to 64%, the hydroxyproline content by up to 91% and the number of myofibroblasts by up to 91%.

LXRα-, β- and LXRα/β-knockout mice showed a similar response to bleomycin challenge as wildtype animals. In line with these results, low levels of the LXR target gene ABCA-1 in the skin of bleomycin-challenged and control mice suggested a weak baseline activation of the anti-fibrotic LXR signaling, which, however, could be specifically activated by T0901317. The specificity of T0901317 on LXRs was again reflected by the LXRα/β-knockout mice in which the LXR agonist lacked anti-fibrotic activity.

Of note, fibroblasts were not the direct targets of the anti-fibrotic effects of LXRs. By contrast, LXR activation inhibited macrophage infiltration in fibrotic tissue and decreased the release of the pro-fibrotic cytokine interleukin-6 from macrophages, resulting in reduced fibroblast activation and collagen release.

Conclusion: We identified LXRs as novel therapeutic targets for SSc and other fibrotic diseases, a yet unknown aspect of these nuclear receptors. Our data suggest that LXR activation might be particularly effective in patients with inflammatory disease subtypes. Activation of LXR interfered with the release of interleukin-6 from macrophages and, thus, inhibited fibroblast activation and collagen release.

Disclosure:

C. Beyer,
None;

J. Beer,
None;

K. Palumbo-Zerr,
None;

P. Zerr,
None;

A. Distler,
None;

C. Dees,
None;

L. E. Munoz,
None;

G. Krönke,
None;

O. Distler,
None;

S. Anderson,
None;

G. A. Schett,
None;

J. H. W. Distler,
None.

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