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

Koenen, Mascha; Culemann, Stephan; Vettorazzi, Sabine; Caratti, Giorgio; Frappart, Lucien; Baum, Wolfgang; Krönke, Gerhard; Baschant, Ulrike; Tuckermann, Jan P.

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

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Item Type:	Article
Title:	Glucocorticoid receptor in stromal cells is essential for glucocorticoid-mediated suppression of inflammation in arthritis
Creators:	Koenen, Mascha ORCID: https://orcid.org/0000-0002-1024-4506, Culemann, Stephan, Vettorazzi, Sabine, Caratti, Giorgio, Frappart, Lucien, Baum, Wolfgang, Krönke, Gerhard, Baschant, Ulrike and Tuckermann, Jan P.
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 (GR(dim)) 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 GR(dim) 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 (Ly6C(neg), MHCII(neg)) 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 GR(dim) 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.
Keywords:	Anti-Inflammatory Agents, Cytokines, Dexamethasone, Dimerization, Experimental Arthritis, Gene Expression Regulation, Glucocorticoid Receptors, Glucocorticoids, Inborn Errors Metabolism, Inbred BALB C Mice, Inbred C57BL Mice, Rheumatoid Arthritis, Stromal Cells, Synoviocytes, Transplantation Chimera, Animals, Mice
Source:	Annals of the Rheumatic Diseases
ISSN:	0003-4967
Publisher:	BMJ Publishing Group
Volume:	77
Number:	11
Page Range:	1610-1618
Date:	November 2018
Official Publication:	https://doi.org/10.1136/annrheumdis-2017-212762
PubMed:	View item in PubMed

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