SFEBES2021 Poster Presentations Metabolism, Obesity and Diabetes (78 abstracts)
Chronic inflammation regulates androgen metabolism and exposure in Macrophages
Claire S Martin 1 , Matthew Singh Kalirai 1 , Ana Crastin 1,2 , Jason D Turner 3 , Lina Schiffer 1 , Lorna C Gilligan 1 , Angela E Taylor 1 , Dagmar Scheel-Toellner 3 , Karim Raza 3 , Andrew Filer 3 , Simon W Jones 3 , Wiebke Arlt 1 , Martin Hewison 1 & Rowan S Hardy 1,2,3
1Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, United Kingdom; 2Institute of Clinical Sciences, University of Birmingham, Birmingham, United Kingdom; 3Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom
Active androgens exert immunomodulatory actions at sites of inflammation and lower levels are implicated in the increased incidence of rheumatoid arthritis (RA) in females. However, inflammatory regulation of intracrine androgen metabolism within cell populations at sites of inflammation remain poorly defined. In this study we characterised immune and stromal cell androgen metabolism in RA patients and assessed their functional significance. Using the online Accelerating Medicines Partnership (AMP) RA dataset, bulk RNA sequencing data from FACS-sorted synovial macrophages, fibroblasts, T cells and B cells were analysed. Expression of 132 steroid hormone receptor, transporter and enzyme genes were analysed in 35 RA patients (27 female, 8 male). Androgen metabolism and its functional effects was determined in RA synovial fluids and primary human macrophage cultures using LC-MS/MS, RT-qPCR and ELISA. Examination of RNA sequencing data from macrophages showed that 5 steroid metabolism genes were significantly (greater than 2-fold, P < 0.05) differentially expressed across inflammation severity (as measured by DAS28-CRP), more than in other cell types assessed. Androgen metabolism pathways showed the greatest relationship with inflammation, with androgen activating enzyme AKR1C3 reduced 4-fold (P < 0.001) in low inflammation compared to high inflammation RA. Analysis of synovial fluids from RA patients revealed quantifiable concentrations of the downstream substrates of AKR1C3, namely DHEA and androstenedione, with metabolite ratios suggesting enzyme dysregulation with inflammation. In primary human monocyte-derived macrophages, pro-inflammatory cytokines, including TNFα (10ng/ml) and IFNγ (20ng/ml), significantly downregulated AKR1C3 in vitro. Incubation of macrophages with the androgen precursor androstenedione (10nmol/l) and the active androgen dihydrotestosterone (10nmol/l) resulted in a marked suppression of the inflammatory cytokines TNFα and IL6, and upregulation of pro-resolution marker CD163. These data reveal novel inflammatory regulation of androgen metabolism in chronic inflammation in macrophages, identifying a putative key role of the androgen-activating enzyme AKR1C3 and demonstrating potent anti-inflammatory effects of androgens in macrophages.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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