Del-1, an Endogenous Inhibitor of TGF-β Activation, Attenuates Fibrosis

Dong Young Kim, Seung Hwan Lee, Yan Fu, Feifeng Jing, Won Young Kim, Sang Bum Hong, Jung A. Song, Han Choe, Hyun Jin Ryu, Minjung Kim, Dahae Lim, Min Seon Kim, Chae Ok Yun, Taewon Lee, Hoon Hyun, Eun Young Choi

Research output: Contribution to journalArticle

Abstract

Uncontrolled activation of transforming growth factor (TGF)-β results in a wide range of pathologic conditions. Therapeutic interventions to regulate TGF-β signaling during fibrosis have been developed but the effectiveness is still limited. Here, we show that developmental endothelial locus-1 (Del-1) ameliorates fibrosis in mice by inhibiting αv integrin-mediated activation of TGF-β. Del-1 bound to αvβ6 integrin, an important activator of TGF-β, and inhibited the binding of αvβ6 integrin to the latency-associated peptide (LAP), thereby suppressing αv integrin-mediated activation of TGF-β. Lack of Del-1 increased colocalization of αv integrin and LAP in the lungs, which was reversed by Del-1 supplementation. The crucial role of Del-1 in regulating TGF-β activity was recapitulated in a mouse model of fibrosis using an adenovirus expressing inactive TGF-β1. Del-1 supplementation improved the pathological characteristics of the mice and reduced mortality. Thus, we propose that Del-1 is a negative regulator of TGF-β activation and a potential anti-fibrotic factor.

Original languageEnglish
Article number68
JournalFrontiers in immunology
Volume11
DOIs
StatePublished - 2020 Feb 7

Keywords

  • Del-1 (developmental endothelial locus-1)
  • fibrosis
  • inflammation
  • integrins
  • transforming growth factor-beta activation

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