Inflammation dynamically regulates steroid hormone metabolism and action within macrophages in rheumatoid arthritis

• Published in: Journal of autoimmunity 2024-07, Vol.147, p.103263, Article 103263
• Main Authors: Martin, C.S, Crastin, A., Sagmeister, M.S., Kalirai, M.S., Turner, J.D., MacDonald, L., Kurowska-Stolarska, M., Scheel-Toellner, D., Taylor, A.E., Gilligan, L.C., Storbeck, K., Price, M., Gorvin, C.M., A, Filer, Mahida, R., Clark, A.R., Jones, S.W., Raza, K., Hewison, M., Hardy, R.S.
• Format: Article
• Language: English
• Subjects: 11-beta-Hydroxysteroid Dehydrogenase Type 1 - genetics; 11-beta-Hydroxysteroid Dehydrogenase Type 1 - metabolism; 3-Oxo-5-alpha-Steroid 4-Dehydrogenase - genetics; 3-Oxo-5-alpha-Steroid 4-Dehydrogenase - metabolism; Aldo-Keto Reductase Family 1 Member C3 - metabolism; Androgens; Arthritis, Rheumatoid - immunology; Arthritis, Rheumatoid - metabolism; Arthritis, Rheumatoid - pathology; Cells, Cultured; Female; Gene Expression Regulation; Glucocorticoids; Glucocorticoids - metabolism; Humans; Hydroxysteroid Dehydrogenases; Inflammation - immunology; Inflammation - metabolism; Macrophage; Macrophages - immunology; Macrophages - metabolism; Male; Membrane Proteins - genetics; Membrane Proteins - metabolism; Rheumatoid arthritis; Steroid metabolism; Steroids - metabolism; Synovial Fluid - immunology; Synovial Fluid - metabolism; Synovial Membrane - immunology; Synovial Membrane - metabolism; Synovial Membrane - pathology
• ISSN: 0896-8411; 1095-9157; 1095-9157
• DOI: 10.1016/j.jaut.2024.103263

In inflammatory diseases such as rheumatoid arthritis (RA), steroid metabolism is a central component mediating the actions of immuno-modulatory glucocorticoids and sex steroids. However, the regulation and function of cellular steroid metabolism within key leukocyte populations such as macrophages remain poorly defined. In this study, the inflammatory regulation of global steroid metabolism was assessed in RA macrophages. Bulk RNA-seq data from RA synovial macrophages was used to assess transcripts encoding key enzymes in steroid metabolism and signalling. Changes in metabolism were assessed in synovial fluids, correlated to measures of disease activity and functionally validated in primary macrophage cultures. RNA-seq revealed a unique pattern of differentially expressed genes, including changes in genes encoding the enzymes 11β-HSD1, SRD5A1, AKR1C2 and AKR1C3. These correlated with disease activity, favouring increased glucocorticoid and androgen levels. Synovial fluid 11β-HSD1 activity correlated with local inflammatory mediators (TNFα, IL-6, IL-17), whilst 11β-HSD1, SRD5A1 and AKR1C3 activity correlated with systemic measures of disease and patient pain (ESR, DAS28 ESR, global disease activity). Changes in enzyme activity were evident in inflammatory activated macrophages in vitro and revealed a novel androgen activating role for 11β-HSD1. Together, increased glucocorticoids and androgens were able to suppress inflammation in macrophages and fibroblast-like-synoviocytes. This study underscores the significant increase in androgen and glucocorticoid activation within inflammatory polarized macrophages of the synovium, contributing to local suppression of inflammation. The diminished profile of inactive steroid precursors in postmenopausal women may contribute to disturbances in this process, leading to increased disease incidence and severity. Schematic of changes in steroid metabolism in inflammatory activated macrophages that favour increased synthesis of the active androgen Dihydrotestosterone (DHT) and the active glucocorticoid cortisol (F). The local activation suppresses pro-inflammatory profiles in macrophages and attenuates TNFα driven synovial fibroblast hyperproliferation. [Display omitted] •In patients with rheumatoid arthritis, inflammatory macrophages are engines of steroid metabolism, generating androgens and glucocorticoids•These glucocorticoids and androgens are immunomodulatory, suppressing inflammatory cytokine profiles and attenuatin