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; Seulki Lee

doi:10.1038/s41467-019-09101-4

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

Nat Commun. 2019 Mar 8;10(1):1128. doi: 10.1038/s41467-019-09101-4.

Authors

Jong-Sung Park^#^{1

2}, Yumin Oh^#^{1

2}, Yong Joo Park^{1

2}, Ogyi Park^{1

2

3}, Hoseong Yang⁴, Stephanie Slania⁵, Laura K Hummers⁶, Ami A Shah⁶, Hyoung-Tae An^{1

2}, Jiyeon Jang^{1

2}, Maureen R Horton⁷, Joseph Shin⁸, Harry C Dietz⁸, Eric Song⁹, Dong Hee Na¹⁰, Eun Ji Park¹⁰, Kwangmeyung Kim¹¹, Kang Choon Lee¹², Viktor V Roschke³, Justin Hanes^{2

5}, Martin G Pomper^{1

13}, Seulki Lee^{14

15

16}

Affiliations

¹ Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, 21205, MD, USA.
² Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, 21205, MD, USA.
³ Theraly Fibrosis Inc., Germantown, 20876, MD, USA.
⁴ Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, 21205, MD, USA.
⁵ Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, 21205, MD, USA.
⁶ Scleroderma Center, Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, 21224, MD, USA.
⁷ Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, 21205, MD, USA.
⁸ McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, 21205, MD, USA.
⁹ Department of Immunobiology, Yale University School of Medicine, New Haven, 06520, CT, USA.
¹⁰ College of Pharmacy, Chung-Ang University, Seoul, 06974, Republic of Korea.
¹¹ Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea.
¹² School of Pharmacy, SungKyunKwan University, Jangangu, 16419, Suwon, Republic of Korea.
¹³ Department of Materials and Science, Johns Hopkins University, Baltimore, 21218, MD, USA.
¹⁴ Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, 21205, MD, USA. [email protected].
¹⁵ Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, 21205, MD, USA. [email protected].
¹⁶ Department of Materials and Science, Johns Hopkins University, Baltimore, 21218, MD, USA. [email protected].

^# Contributed equally.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Actins / genetics*
Actins / metabolism
Adult
Aged
Animals
Apoptosis / drug effects
Apoptosis / genetics
Cell Differentiation
Collagen / genetics
Collagen / metabolism
Dermis / drug effects*
Dermis / metabolism
Dermis / pathology
Disease Models, Animal
Female
Fibroblasts / drug effects
Fibroblasts / metabolism
Fibroblasts / pathology
Fibrosis
Gene Expression Regulation
Humans
Male
Mice
Middle Aged
Molecular Targeted Therapy
Myofibroblasts / drug effects*
Myofibroblasts / metabolism
Myofibroblasts / pathology
Protein Engineering
Receptors, TNF-Related Apoptosis-Inducing Ligand / agonists
Receptors, TNF-Related Apoptosis-Inducing Ligand / genetics*
Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism
Scleroderma, Systemic / drug therapy*
Scleroderma, Systemic / genetics
Scleroderma, Systemic / immunology
Scleroderma, Systemic / pathology
Signal Transduction
TNF-Related Apoptosis-Inducing Ligand / pharmacology*

Substances

Actins
Receptors, TNF-Related Apoptosis-Inducing Ligand
TNF-Related Apoptosis-Inducing Ligand
TNFSF10 protein, human
alpha-smooth muscle actin, mouse
Collagen

Abstract

Publication types

MeSH terms

Substances

Grants and funding