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 2024-01-19T20:33:27Z 2024-01-19T20:33:27Z 2021-09-02 2019-03 2041-1723 https://pubs.kist.re.kr/handle/201004/120293 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. English Nature Publishing Group Targeting of dermal myofibroblasts through death receptor 5 arrests fibrosis in mouse models of scleroderma Article 10.1038/s41467-019-09101-4 1 Nature Communications, v.10 Nature Communications 10 Y scie scopus 000460631100013 2-s2.0-85062630746 Multidisciplinary Sciences Science & Technology - Other Topics Article SYSTEMIC-SCLEROSIS ANTITUMOR-ACTIVITY STELLATE CELLS APOPTOSIS BETA EXPRESSION CHALLENGES RESISTANCE PATHWAYS