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

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 HanesMartin G. Pomper, Seulki Lee

Research output: Contribution to journal › Article › peer-review

18 Citations (Scopus)

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.

Original language	English
Article number	1128
Journal	Nature communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-09101-4
Publication status	Published - 2019 Dec 1
Externally published	Yes

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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10.1038/s41467-019-09101-4

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Park, J. S., Oh, Y., Park, Y. J., Park, O., Yang, H., Slania, S., Hummers, L. K., Shah, A. A., An, H. T., Jang, J., Horton, M. R., Shin, J., Dietz, H. C., Song, E., Na, D. H., Park, E. J., Kim, K., Lee, K. C., Roschke, V. V., ... Lee, S. (2019). Targeting of dermal myofibroblasts through death receptor 5 arrests fibrosis in mouse models of scleroderma. Nature communications, 10(1), [1128]. https://doi.org/10.1038/s41467-019-09101-4

Park, JS, Oh, Y, Park, YJ, Park, O, Yang, H, Slania, S, Hummers, LK, Shah, AA, An, HT, Jang, J, Horton, MR, Shin, J, Dietz, HC, Song, E, Na, DH, Park, EJ, Kim, K, Lee, KC, Roschke, VV, Hanes, J, Pomper, MG & Lee, S 2019, 'Targeting of dermal myofibroblasts through death receptor 5 arrests fibrosis in mouse models of scleroderma', Nature communications, vol. 10, no. 1, 1128. https://doi.org/10.1038/s41467-019-09101-4

@article{f5b6a33d77be4bffa82a418537baa6b5,

title = "Targeting of dermal myofibroblasts through death receptor 5 arrests fibrosis in mouse models of scleroderma",

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.",

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

note = "Funding Information: This work was supported by grants from the Department of Defense (W81XWH-15-1-0301, W81XWH-14-1-0239), National Institutes of Health (1U44AA026111-01), Maryland Technology Development Corporation (2016-MII-4352), and the National Research Foundation of Korea (NRF-2013K1A1A2A02050115, NRF-2016R1A2B4006914, NRF-2018R1A2B3004266). The authors acknowledge the joint participation by the Donald B. & Dorothy L. Stabler Foundation and the Jerome L. Greene Fund and the Scleroderma Research Foundation. We thank F.M. Wigley for providing SSc cell lines, A. Bora for editing the manuscript and Theraly Fibrosis Inc. for providing TLY012. Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2019",

month = dec,

day = "1",

doi = "10.1038/s41467-019-09101-4",

language = "English",

volume = "10",

journal = "Nature Communications",

issn = "2041-1723",

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TY - JOUR

T1 - Targeting of dermal myofibroblasts through death receptor 5 arrests fibrosis in mouse models of scleroderma

AU - Park, Jong Sung

AU - Oh, Yumin

AU - Park, Yong Joo

AU - Park, Ogyi

AU - Yang, Hoseong

AU - Slania, Stephanie

AU - Hummers, Laura K.

AU - Shah, Ami A.

AU - An, Hyoung Tae

AU - Jang, Jiyeon

AU - Horton, Maureen R.

AU - Shin, Joseph

AU - Dietz, Harry C.

AU - Song, Eric

AU - Na, Dong Hee

AU - Park, Eun Ji

AU - Kim, Kwangmeyung

AU - Lee, Kang Choon

AU - Roschke, Viktor V.

AU - Hanes, Justin

AU - Pomper, Martin G.

AU - Lee, Seulki

N1 - Funding Information: This work was supported by grants from the Department of Defense (W81XWH-15-1-0301, W81XWH-14-1-0239), National Institutes of Health (1U44AA026111-01), Maryland Technology Development Corporation (2016-MII-4352), and the National Research Foundation of Korea (NRF-2013K1A1A2A02050115, NRF-2016R1A2B4006914, NRF-2018R1A2B3004266). The authors acknowledge the joint participation by the Donald B. & Dorothy L. Stabler Foundation and the Jerome L. Greene Fund and the Scleroderma Research Foundation. We thank F.M. Wigley for providing SSc cell lines, A. Bora for editing the manuscript and Theraly Fibrosis Inc. for providing TLY012. Publisher Copyright: © 2019, The Author(s).

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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.

AB - 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.

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DO - 10.1038/s41467-019-09101-4

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AN - SCOPUS:85062630746

SN - 2041-1723

VL - 10

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 1128

ER -

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

Abstract

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