Glucocorticoid receptor in stromal cells is essential for glucocorticoid-mediated suppression of inflammation in arthritis

Journal article


Publication Details

Author(s): Koenen M, Koenen M, Culemann S, Vettorazzi S, Caratti G, Caratti G, Frappart L, Baum W, Krönke G, Baschant U, Tuckermann JP
Journal: Annals of the Rheumatic Diseases
Publication year: 2018
Volume: 77
Journal issue: 11
Pages range: 1610-1618
ISSN: 0003-4967


Abstract

BACKGROUND: Glucocorticoid (GC) therapy is frequently used to treat rheumatoid arthritis due to potent anti-inflammatory actions of GCs. Direct actions of GCs on immune cells were suggested to suppress inflammation.
OBJECTIVES: Define the role of the glucocorticoid receptor (GR) in stromal cells for suppression of inflammatory arthritis.
METHODS: Bone marrow chimeric mice lacking the GR in the hematopoietic or stromal compartment, respectively, and mice with impaired GR dimerisation (GRdim) were analysed for their response to dexamethasone (DEX, 1 mg/kg) treatment in serum transfer-induced arthritis (STIA). Joint swelling, cell infiltration (histology), cytokines, cell composition (flow cytometry) and gene expression were analysed and RNASeq of wild type and GRdim primary murine fibroblast-like synoviocytes (FLS) was performed.
RESULTS: GR deficiency in immune cells did not impair GC-mediated suppression of STIA. In contrast, mice with GR-deficient or GR dimerisation-impaired stromal cells were resistant to GC treatment, despite efficient suppression of cytokines. Intriguingly, in mice with impaired GR function in the stromal compartment, GCs failed to stimulate non-classical, non-activated macrophages (Ly6Cneg, MHCIIneg) and associated anti-inflammatory markers CD163, CD36, AnxA1, MerTK and Axl. Mice with GR deficiency in FLS were partially resistant to GC-induced suppression of STIA. Accordingly, RNASeq analysis of DEX-treated GRdim FLS revealed a distinct gene signature indicating enhanced activity and a failure to reduce macrophage inflammatory protein (Mip)-1α and Mip-1β.
CONCLUSION: We report a novel anti-inflammatory mechanism of GC action that involves GR dimerisation-dependent gene regulation in non-immune stromal cells, presumably FLS. FLS control non-classical, anti-inflammatory polarisation of macrophages that contributes to suppression of inflammation in arthritis.


FAU Authors / FAU Editors

Krönke, Gerhard Prof. Dr. med.
Medizinische Klinik 3 - Rheumatologie und Immunologie


External institutions
Leibniz-Institut für Alternsforschung - Fritz-Lipmann-Institut (FLI)
Universität Ulm


How to cite

APA:
Koenen, M., Koenen, M., Culemann, S., Vettorazzi, S., Caratti, G., Caratti, G.,... Tuckermann, J.P. (2018). Glucocorticoid receptor in stromal cells is essential for glucocorticoid-mediated suppression of inflammation in arthritis. Annals of the Rheumatic Diseases, 77(11), 1610-1618. https://dx.doi.org/10.1136/annrheumdis-2017-212762

MLA:
Koenen, Mascha, et al. "Glucocorticoid receptor in stromal cells is essential for glucocorticoid-mediated suppression of inflammation in arthritis." Annals of the Rheumatic Diseases 77.11 (2018): 1610-1618.

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Last updated on 2019-07-01 at 10:38