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TRAIL regulatory receptors constrain human hepatic stellate cell apoptosis

Harsimran D Singh1,2, Itziar Otano1, Krista Rombouts2

  • 1Division of Infection and Immunity, UCL, London, UK.

Scientific Reports
|July 19, 2017
PubMed

Insights

Regulatory TRAIL receptors (TRAIL-R3/4) protect human hepatic stellate cells (hHSC) from apoptosis, impacting liver fibrosis progression. Targeting these receptors may offer new therapeutic strategies for liver fibrosis.

Area of Science:

  • Immunology
  • Cell Biology
  • Hepatology

Background:

  • The Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) pathway induces apoptosis in hepatic stellate cells (hHSC), aiding liver fibrosis resolution.
  • TRAIL interacts with both death-inducing and regulatory receptors, but the roles of regulatory receptors in liver fibrosis remain unclear.

Purpose of the Study:

  • To investigate the contribution of regulatory TRAIL receptors to apoptosis resistance in primary human hepatic stellate cells (hHSC).
  • To determine the functional roles of TRAIL-R1, TRAIL-R2, TRAIL-R3, and TRAIL-R4 in regulating hHSC apoptosis and liver fibrosis.

Main Methods:

  • Primary human hepatic stellate cells (hHSC) were isolated and analyzed for TRAIL receptor expression (TRAIL-R1/2/3/4).
  • Lentiviral-mediated knockdown and shRNA knockdown were used to assess the function of TRAIL-R2, TRAIL-R3, and TRAIL-R4.
  • Monoclonal antibody (mAb) blockade was employed to inhibit regulatory TRAIL receptors.

Main Results:

  • hHSC expressed variable levels of TRAIL-R2/3/4, with negligible TRAIL-R1.
  • Knockdown of TRAIL-R2 confirmed its apoptotic potential on hHSC.
  • Knockdown and blockade of TRAIL-R3/4 revealed their inhibitory role, limiting hHSC apoptosis induced by TRAIL and NK cells.
  • A strong inverse correlation was observed between TRAIL-R4 expression and hHSC apoptosis susceptibility.

Conclusions:

  • TRAIL-R3 and TRAIL-R4 act as non-redundant inhibitory receptors, protecting hHSC from apoptosis in a physiological context.
  • These findings highlight the critical role of regulatory TRAIL receptors in controlling hHSC apoptosis.
  • Targeting inhibitory TRAIL receptors presents novel prognostic and therapeutic opportunities for managing liver fibrosis.

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