Journal Article

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

Park, Jong-Sung, Shin, Joseph, Pomper, Martin G., Hanes, Justin, Lee, Seulki, Song, Eric, Park, Eun Ji, Oh, Yumin, Horton, Maureen R., An, Hyoung-Tae, Hummers, Laura K., Jang, Jiyeon, Park, Yong Joo, Dietz, Harry C., Shah, Ami A., Kim, Kwangmeyung, Park, Ogyi, Slania, Stephanie, Roschke, Viktor V., Na, Dong Hee, Lee, Kang Choon, Yang, Hoseong

2019

Overview

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. Dermal myofibroblasts are responsible for fibrosis development in scleroderma. Here the authors show that a bioengineered recombinant human TRAIL ligand reverses established fibrosis in mouse models of scleroderma by targeting the death receptor 5 and inducing apoptosis of myofibroblasts.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/2 / 631/80/82/23 / 64/60 / 692/699/1670/122/1801 / 692/700/565 / Actin / Actins - genetics / Actins - metabolism / Activation / Adult / Aged / Animal models / Animals / Apoptosis / Apoptosis - drug effects / Apoptosis - genetics / Cell Differentiation / Collagen / Collagen - genetics / Collagen - metabolism / Death receptors / Dermis - drug effects / Dermis - metabolism / Dermis - pathology / Disease Models, Animal / Female / Fibroblasts / Fibroblasts - drug effects / Fibroblasts - metabolism / Fibroblasts - pathology / Fibrosis / Gene Expression Regulation / Humanities and Social Sciences / Humans / Male / Mice / Middle Aged / Molecular Targeted Therapy / Mortality / multidisciplinary / Muscles / Myofibroblasts - drug effects / Myofibroblasts - metabolism / Myofibroblasts - pathology / Organs / Protein Engineering / Receptors / Receptors, TNF-Related Apoptosis-Inducing Ligand - agonists / Receptors, TNF-Related Apoptosis-Inducing Ligand - genetics / Receptors, TNF-Related Apoptosis-Inducing Ligand - metabolism / Rheumatic diseases / Science / Science (multidisciplinary) / Scleroderma / Scleroderma, Systemic - drug therapy / Scleroderma, Systemic - genetics / Scleroderma, Systemic - immunology / Scleroderma, Systemic - pathology / Signal Transduction / Skin / Smooth muscle / Therapeutic applications / TNF-Related Apoptosis-Inducing Ligand - pharmacology / TRAIL protein / Transformed cells