Targeting of dermal myofibroblasts through death receptor 5 arrests fibrosis in mouse models of scleroderma
- Authors
- Park, Jong-Sung; Oh, Yumin; Park, Yong Joo; Park, Ogyi; Yang, Hoseong; Slania, Stephanie; Hummers, Laura K.; Shah, Ami A.; An, Hyoung-Tae; Jang, Jiyeon; Horton, Maureen R.; Shin, Joseph; Dietz, Harry C.; Song, Eric; Na, Dong Hee; Park, Eun Ji; Kim, Kwangmeyung; Lee, Kang Choon; Roschke, Viktor V.; Hanes, Justin; Pomper, Martin G.; Lee, Seulki
- Issue Date
- 2019-03
- Publisher
- Nature Publishing Group
- Citation
- Nature Communications, v.10
- Abstract
- Scleroderma is an autoimmune rheumatic disorder accompanied by severe fibrosis in skin and other internal organs. During scleroderma progression, resident fibroblasts undergo activation and convert to alpha-smooth muscle actin (alpha-SMA) expressing myofibroblasts (MFBs) with increased capacity to synthesize collagens and fibrogenic components. Accordingly, MFBs are a major therapeutic target for fibrosis in scleroderma and treatment with blocking MFBs could produce anti-fibrotic effects. TLY012 is an engineered human TNF-related apoptosis-inducing ligand (TRAIL) which induces selective apoptosis in transformed cells expressing its cognate death receptors (DRs). Here we report that TLY012 selectively blocks activation of dermal fibroblasts and induces DR-mediated apoptosis in alpha-SMA(+) MFBs through upregulated DR5 during its activation. In vivo, TLY012 reverses established skin fibrosis to near-normal skin architecture in mouse models of scleroderma. Thus, the TRAIL pathway plays a critical role in tissue remodeling and targeting upregulated DR5 in alpha-SMA(+) MFBs is a viable therapy for fibrosis in scleroderma.
- Keywords
- SYSTEMIC-SCLEROSIS; ANTITUMOR-ACTIVITY; STELLATE CELLS; APOPTOSIS; BETA; EXPRESSION; CHALLENGES; RESISTANCE; PATHWAYS
- ISSN
- 2041-1723
- URI
- https://pubs.kist.re.kr/handle/201004/120293
- DOI
- 10.1038/s41467-019-09101-4
- Appears in Collections:
- KIST Article > 2019
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