Frontiers in Immunology (Feb 2020)

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

DOI
https://doi.org/10.3389/fimmu.2020.00068
Journal volume & issue
Vol. 11

Abstract

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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.

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