Adipocyte associated glucocorticoid signaling regulates normal fibroblast function which is lost in inflammatory arthritis
Abstract 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 progra...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-11-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-52586-x |
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| author | Heather J. Faust Tan-Yun Cheng Ilya Korsunsky Gerald F. M. Watts Shani T. Gal-Oz William V. Trim Suppawat Kongthong Anna Helena Jonsson Daimon P. Simmons Fan Zhang Robert Padera Susan Chubinskaya Accelerating Medicines Partnership: RA/SLE Network Kevin Wei Soumya Raychaudhuri Lydia Lynch D. Branch Moody Michael B. Brenner |
| author_facet | Heather J. Faust Tan-Yun Cheng Ilya Korsunsky Gerald F. M. Watts Shani T. Gal-Oz William V. Trim Suppawat Kongthong Anna Helena Jonsson Daimon P. Simmons Fan Zhang Robert Padera Susan Chubinskaya Accelerating Medicines Partnership: RA/SLE Network Kevin Wei Soumya Raychaudhuri Lydia Lynch D. Branch Moody Michael B. Brenner |
| author_sort | Heather J. Faust |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-3e5e65bb0f064db6ad29ea13b28c4dd7 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-3e5e65bb0f064db6ad29ea13b28c4dd72024-12-08T12:36:37ZengNature PortfolioNature Communications2041-17232024-11-0115112010.1038/s41467-024-52586-xAdipocyte associated glucocorticoid signaling regulates normal fibroblast function which is lost in inflammatory arthritisHeather J. Faust0Tan-Yun Cheng1Ilya Korsunsky2Gerald F. M. Watts3Shani T. Gal-Oz4William V. Trim5Suppawat Kongthong6Anna Helena Jonsson7Daimon P. Simmons8Fan Zhang9Robert Padera10Susan Chubinskaya11Accelerating Medicines Partnership: RA/SLE NetworkKevin Wei12Soumya Raychaudhuri13Lydia Lynch14D. Branch Moody15Michael B. Brenner16Division of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital and Harvard Medical SchoolDivision of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital and Harvard Medical SchoolDivision of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital and Harvard Medical SchoolDivision of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital and Harvard Medical SchoolDivision of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital and Harvard Medical SchoolDepartment of Endocrinology, Brigham and Women’s Hospital and Harvard Medical SchoolDivision of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital and Harvard Medical SchoolDivision of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital and Harvard Medical SchoolDivision of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital and Harvard Medical SchoolDivision of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital and Harvard Medical SchoolDepartment of Pathology, Brigham and Women’s HospitalDepartment of Pediatrics, Rush Medical CollegeDivision of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital and Harvard Medical SchoolDivision of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital and Harvard Medical SchoolDepartment of Endocrinology, Brigham and Women’s Hospital and Harvard Medical SchoolDivision of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital and Harvard Medical SchoolDivision of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital and Harvard Medical SchoolAbstract 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.https://doi.org/10.1038/s41467-024-52586-x |
| spellingShingle | Heather J. Faust Tan-Yun Cheng Ilya Korsunsky Gerald F. M. Watts Shani T. Gal-Oz William V. Trim Suppawat Kongthong Anna Helena Jonsson Daimon P. Simmons Fan Zhang Robert Padera Susan Chubinskaya Accelerating Medicines Partnership: RA/SLE Network Kevin Wei Soumya Raychaudhuri Lydia Lynch D. Branch Moody Michael B. Brenner Adipocyte associated glucocorticoid signaling regulates normal fibroblast function which is lost in inflammatory arthritis Nature Communications |
| title | Adipocyte associated glucocorticoid signaling regulates normal fibroblast function which is lost in inflammatory arthritis |
| title_full | Adipocyte associated glucocorticoid signaling regulates normal fibroblast function which is lost in inflammatory arthritis |
| title_fullStr | Adipocyte associated glucocorticoid signaling regulates normal fibroblast function which is lost in inflammatory arthritis |
| title_full_unstemmed | Adipocyte associated glucocorticoid signaling regulates normal fibroblast function which is lost in inflammatory arthritis |
| title_short | Adipocyte associated glucocorticoid signaling regulates normal fibroblast function which is lost in inflammatory arthritis |
| title_sort | adipocyte associated glucocorticoid signaling regulates normal fibroblast function which is lost in inflammatory arthritis |
| url | https://doi.org/10.1038/s41467-024-52586-x |
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