Targeting of dermal myofibroblasts through death receptor 5 arrests fibrosis in mouse models of scleroderma
- Targeting of dermal myofibroblasts through death receptor 5 arrests fibrosis in mouse models of scleroderma
- 김광명; Jong-Sung Park; Yumin Oh; Yong Joo Park; Ogyi Park; Hoseong Yang; Stephanie Slania; Laura K. Hummers; Ami A. Shah; Hyoung-Tae An; Jiyeon Jang; Maureen R. Horton; Joseph Shin; Harry C. Dietz; Eric Song; Dong Hee Na; Eun Ji Park; Kang Choon Lee; Viktor V. Roschke; Justin Hanes; Martin G. Pomper; Seulki Lee
- Issue Date
- Nature Communications
- VOL 10-1128-11
- 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 α-smooth muscle actin (α-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 α-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 α-SMA+ MFBs is a viable therapy for fibrosis in scleroderma.
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