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

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, Kwangmeyung Kim, Kang Choon Lee, Viktor V. Roschke, Justin Hanes, Martin G. Pomper and Seulki Lee ()
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Jong-Sung Park: Johns Hopkins University School of Medicine
Yumin Oh: Johns Hopkins University School of Medicine
Yong Joo Park: Johns Hopkins University School of Medicine
Ogyi Park: Johns Hopkins University School of Medicine
Hoseong Yang: Johns Hopkins University School of Medicine
Stephanie Slania: Johns Hopkins University School of Medicine
Laura K. Hummers: Johns Hopkins University School of Medicine
Ami A. Shah: Johns Hopkins University School of Medicine
Hyoung-Tae An: Johns Hopkins University School of Medicine
Jiyeon Jang: Johns Hopkins University School of Medicine
Maureen R. Horton: Johns Hopkins University School of Medicine
Joseph Shin: Johns Hopkins University School of Medicine
Harry C. Dietz: Johns Hopkins University School of Medicine
Eric Song: Yale University School of Medicine
Dong Hee Na: Chung-Ang University
Eun Ji Park: Chung-Ang University
Kwangmeyung Kim: Korea Institute of Science and Technology
Kang Choon Lee: SungKyunKwan University
Viktor V. Roschke: Theraly Fibrosis Inc.
Justin Hanes: Johns Hopkins University School of Medicine
Martin G. Pomper: Johns Hopkins University School of Medicine
Seulki Lee: Johns Hopkins University School of Medicine

Nature Communications, 2019, vol. 10, issue 1, 1-11

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-09101-4

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