Targeting of dermal myofibroblasts through death receptor 5 arrests fibrosis in mouse models of scleroderma

Title
Targeting of dermal myofibroblasts through death receptor 5 arrests fibrosis in mouse models of scleroderma
Authors
김광명Jong-Sung ParkYumin OhYong Joo ParkOgyi ParkHoseong YangStephanie SlaniaLaura K. HummersAmi A. ShahHyoung-Tae AnJiyeon JangMaureen R. HortonJoseph ShinHarry C. DietzEric SongDong Hee NaEun Ji ParkKang Choon LeeViktor V. RoschkeJustin HanesMartin G. PomperSeulki Lee
Issue Date
2019-03
Publisher
Nature Communications
Citation
VOL 10-1128-11
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 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.
URI
http://pubs.kist.re.kr/handle/201004/69957
ISSN
2041-1723
Appears in Collections:
KIST Publication > Article
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