Adipocyte associated glucocorticoid signaling regulates normal fibroblast function which is lost in inflammatory arthritis.

Autor: Faust HJ; Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA., Cheng TY; Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA., Korsunsky I; Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.; Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, USA.; Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA., Watts GFM; Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA., Gal-Oz ST; Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA., Trim WV; Department of Endocrinology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA., Kongthong S; Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA., Jonsson AH; Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA., Simmons DP; Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.; Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA., Zhang F; Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.; Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, USA.; Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.; Division of Rheumatology and the Center for Health Artificial Intelligence, University of Colorado School of Medicine, Aurora, CO, USA., Padera R; Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA., Chubinskaya S; Department of Pediatrics, Rush Medical College, Chicago, IL, USA., Wei K; Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA., Raychaudhuri S; Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.; Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, USA.; Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA., Lynch L; Department of Endocrinology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA., Moody DB; Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA., Brenner MB; Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. mbrenner@bwh.harvard.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Nov 14; Vol. 15 (1), pp. 9859. Date of Electronic Publication: 2024 Nov 14.
DOI: 10.1038/s41467-024-52586-x
Abstrakt: Fibroblasts play critical roles in tissue homeostasis, but in pathologic states they can drive fibrosis, inflammation, and tissue destruction. Little is known about what regulates the homeostatic functions of fibroblasts. Here, we perform RNA sequencing and identify a gene expression program in healthy synovial fibroblasts characterized by enhanced fatty acid metabolism and lipid transport. We identify cortisol as the key driver of the healthy fibroblast phenotype and that depletion of adipocytes, which express high levels of Hsd11b1, results in loss of the healthy fibroblast phenotype in mouse synovium. Additionally, fibroblast-specific glucocorticoid receptor Nr3c1 deletion in vivo leads to worsened arthritis. Cortisol signaling in fibroblasts mitigates matrix remodeling induced by TNF and TGF-β1 in vitro, while stimulation with these cytokines represses cortisol signaling and adipogenesis. Together, these findings demonstrate the importance of adipocytes and cortisol signaling in driving the healthy synovial fibroblast state that is lost in disease.
Competing Interests: Competing interests M.B.B. serves on the scientific advisory board for GlaxoSmithKline and as a consultant for Moderna and 4FO ventures. Consulting relates to programs specific to each company and does not directly relate to the research in this report. MBB is the founder of Mestag Therapeutics which is focused on fibroblast-mediated pathology but not directly related to the research in this report. The remaining authors declare no competing interests.
(© 2024. The Author(s).)
Databáze: MEDLINE
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