TRAIL regulatory receptors constrain human hepatic stellate cell apoptosis

Abstract The TRAIL pathway can mediate apoptosis of hepatic stellate cells to promote the resolution of liver fibrosis. However, TRAIL has the capacity to bind to regulatory receptors in addition to death-inducing receptors; their differential roles in liver fibrosis have not been investigated. Here...

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Autores principales:	Harsimran D. Singh, Itziar Otano, Krista Rombouts, Kasha P. Singh, Dimitra Peppa, Upkar S. Gill, Katrin Böttcher, Patrick T. F. Kennedy, Jude Oben, Massimo Pinzani, Henning Walczak, Giuseppe Fusai, William M. C. Rosenberg, Mala K. Maini
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/0c84e0f5a1504bfe85b9a7ea0c3a5f5a
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spelling	oai:doaj.org-article:0c84e0f5a1504bfe85b9a7ea0c3a5f5a2021-12-02T11:52:37ZTRAIL regulatory receptors constrain human hepatic stellate cell apoptosis10.1038/s41598-017-05845-52045-2322https://doaj.org/article/0c84e0f5a1504bfe85b9a7ea0c3a5f5a2017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-05845-5https://doaj.org/toc/2045-2322Abstract The TRAIL pathway can mediate apoptosis of hepatic stellate cells to promote the resolution of liver fibrosis. However, TRAIL has the capacity to bind to regulatory receptors in addition to death-inducing receptors; their differential roles in liver fibrosis have not been investigated. Here we have dissected the contribution of regulatory TRAIL receptors to apoptosis resistance in primary human hepatic stellate cells (hHSC). hHSC isolated from healthy margins of liver resections from different donors expressed variable levels of TRAIL-R2/3/4 (but negligible TRAIL-R1) ex vivo and after activation. The apoptotic potential of TRAIL-R2 on hHSC was confirmed by lentiviral-mediated knockdown. A functional inhibitory role for TRAIL-R3/4 was revealed by shRNA knockdown and mAb blockade, showing that these regulatory receptors limit apoptosis of hHSC in response to both oligomerised TRAIL and NK cells. A close inverse ex vivo correlation between hHSC TRAIL-R4 expression and susceptibility to apoptosis underscored its central regulatory role. Our data provide the first demonstration of non-redundant functional roles for the regulatory TRAIL receptors (TRAIL-R3/4) in a physiological setting. The potential for these inhibitory TRAIL receptors to protect hHSC from apoptosis opens new avenues for prognostic and therapeutic approaches to the management of liver fibrosis.Harsimran D. SinghItziar OtanoKrista RomboutsKasha P. SinghDimitra PeppaUpkar S. GillKatrin BöttcherPatrick T. F. KennedyJude ObenMassimo PinzaniHenning WalczakGiuseppe FusaiWilliam M. C. RosenbergMala K. MainiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Harsimran D. Singh Itziar Otano Krista Rombouts Kasha P. Singh Dimitra Peppa Upkar S. Gill Katrin Böttcher Patrick T. F. Kennedy Jude Oben Massimo Pinzani Henning Walczak Giuseppe Fusai William M. C. Rosenberg Mala K. Maini TRAIL regulatory receptors constrain human hepatic stellate cell apoptosis
description	Abstract The TRAIL pathway can mediate apoptosis of hepatic stellate cells to promote the resolution of liver fibrosis. However, TRAIL has the capacity to bind to regulatory receptors in addition to death-inducing receptors; their differential roles in liver fibrosis have not been investigated. Here we have dissected the contribution of regulatory TRAIL receptors to apoptosis resistance in primary human hepatic stellate cells (hHSC). hHSC isolated from healthy margins of liver resections from different donors expressed variable levels of TRAIL-R2/3/4 (but negligible TRAIL-R1) ex vivo and after activation. The apoptotic potential of TRAIL-R2 on hHSC was confirmed by lentiviral-mediated knockdown. A functional inhibitory role for TRAIL-R3/4 was revealed by shRNA knockdown and mAb blockade, showing that these regulatory receptors limit apoptosis of hHSC in response to both oligomerised TRAIL and NK cells. A close inverse ex vivo correlation between hHSC TRAIL-R4 expression and susceptibility to apoptosis underscored its central regulatory role. Our data provide the first demonstration of non-redundant functional roles for the regulatory TRAIL receptors (TRAIL-R3/4) in a physiological setting. The potential for these inhibitory TRAIL receptors to protect hHSC from apoptosis opens new avenues for prognostic and therapeutic approaches to the management of liver fibrosis.
format	article
author	Harsimran D. Singh Itziar Otano Krista Rombouts Kasha P. Singh Dimitra Peppa Upkar S. Gill Katrin Böttcher Patrick T. F. Kennedy Jude Oben Massimo Pinzani Henning Walczak Giuseppe Fusai William M. C. Rosenberg Mala K. Maini
author_facet	Harsimran D. Singh Itziar Otano Krista Rombouts Kasha P. Singh Dimitra Peppa Upkar S. Gill Katrin Böttcher Patrick T. F. Kennedy Jude Oben Massimo Pinzani Henning Walczak Giuseppe Fusai William M. C. Rosenberg Mala K. Maini
author_sort	Harsimran D. Singh
title	TRAIL regulatory receptors constrain human hepatic stellate cell apoptosis
title_short	TRAIL regulatory receptors constrain human hepatic stellate cell apoptosis
title_full	TRAIL regulatory receptors constrain human hepatic stellate cell apoptosis
title_fullStr	TRAIL regulatory receptors constrain human hepatic stellate cell apoptosis
title_full_unstemmed	TRAIL regulatory receptors constrain human hepatic stellate cell apoptosis
title_sort	trail regulatory receptors constrain human hepatic stellate cell apoptosis
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/0c84e0f5a1504bfe85b9a7ea0c3a5f5a
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_version_	1718394966171975680

TRAIL regulatory receptors constrain human hepatic stellate cell apoptosis

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