ETS1 governs pathological tissue-remodeling programs in disease-associated fibroblasts
SCIE
SCOPUS
- Title
- ETS1 governs pathological tissue-remodeling programs in disease-associated fibroblasts
- Authors
- Yan, Minglu; Komatsu, Noriko; Muro, Ryunosuke; Huynh, Nam Cong-Nhat; Tomofuji, Yoshihiko; Okada, Yukinori; Suzuki, Hiroshi I.; Takaba, Hiroyuki; Kitazawa, Riko; Kitazawa, Sohei; Pluemsakunthai, Warunee; Mitsui, Yuichi; Satoh, Takashi; Okamura, Tadashi; Nitta, Takeshi; Im, Sin-Hyeog; Kim, Chan Johng; Kollias, George; Tanaka, Sakae; Okamoto, Kazuo; Tsukasaki, Masayuki; Takayanagi, Hiroshi
- Date Issued
- 2022-09
- Publisher
- Nature Research
- Abstract
- © 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.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.
- URI
- https://oasis.postech.ac.kr/handle/2014.oak/113890
- DOI
- 10.1038/s41590-022-01285-0
- ISSN
- 1529-2908
- Article Type
- Article
- Citation
- Nature Immunology, vol. 23, no. 9, page. 1330 - 1341, 2022-09
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