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.

journal_name

Nat Commun

journal_title

Nature communications

authors

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

doi

10.1038/s41467-019-09101-4

subject

Has Abstract

pub_date

2019-03-08 00:00:00

pages

1128

issue

1

issn

2041-1723

pii

10.1038/s41467-019-09101-4

journal_volume

10

pub_type

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