| Autor: |
Minglu Yan, Noriko Komatsu, Ryunosuke Muro, Nam Cong-Nhat Huynh, Yoshihiko Tomofuji, Yukinori Okada, Hiroshi I. Suzuki, Hiroyuki Takaba, Riko Kitazawa, Sohei Kitazawa, Warunee Pluemsakunthai, Yuichi Mitsui, Takashi Satoh, Tadashi Okamura, Takeshi Nitta, Sin-Hyeog Im, Chan Johng Kim, George Kollias, Sakae Tanaka, Kazuo Okamoto, Masayuki Tsukasaki, Hiroshi Takayanagi |
| Rok vydání: |
2021 |
| Předmět: |
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| Zdroj: |
Nature immunology. 23(9) |
| ISSN: |
1529-2916 |
| Popis: |
Fibroblasts, the most abundant structural cells, exert homeostatic functions but also drive disease pathogenesis. Single-cell technologies have illuminated the shared characteristics of pathogenic fibroblasts in multiple diseases including autoimmune arthritis, cancer and inflammatory colitis. However, the molecular mechanisms underlying the disease-associated fibroblast phenotypes remain largely unclear. Here, we identify ETS1 as the key transcription factor governing the pathological tissue-remodeling programs in fibroblasts. In arthritis, ETS1 drives polarization toward tissue-destructive fibroblasts by orchestrating hitherto undescribed regulatory elements of the osteoclast differentiation factor receptor activator of nuclear factor-κB ligand (RANKL) as well as matrix metalloproteinases. Fibroblast-specific ETS1 deletion resulted in ameliorated bone and cartilage damage under arthritic conditions without affecting the inflammation level. Cross-tissue fibroblast single-cell data analyses and genetic loss-of-function experiments lent support to the notion that ETS1 defines the perturbation-specific fibroblasts shared among various disease settings. These findings provide a mechanistic basis for pathogenic fibroblast polarization and have important therapeutic implications. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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