Mitigation of sepsis-induced inflammatory responses and organ injury through targeting Wnt/β-catenin signaling

Abstract The Wnt/β-catenin pathway has been involved in regulating inflammation in various infectious and inflammatory diseases. Sepsis is a life-threatening condition caused by dysregulated inflammatory response to infection with no effective therapy available. Recently elevated Wnt/β-catenin signa...

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Autores principales:	Archna Sharma, Weng-Lang Yang, Mahendar Ochani, Ping Wang
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/adcd7b62b5484633bddd183d38ff0f76
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spelling	oai:doaj.org-article:adcd7b62b5484633bddd183d38ff0f762021-12-02T16:08:00ZMitigation of sepsis-induced inflammatory responses and organ injury through targeting Wnt/β-catenin signaling10.1038/s41598-017-08711-62045-2322https://doaj.org/article/adcd7b62b5484633bddd183d38ff0f762017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-08711-6https://doaj.org/toc/2045-2322Abstract The Wnt/β-catenin pathway has been involved in regulating inflammation in various infectious and inflammatory diseases. Sepsis is a life-threatening condition caused by dysregulated inflammatory response to infection with no effective therapy available. Recently elevated Wnt/β-catenin signaling has been detected in sepsis. However, its contribution to sepsis-associated inflammatory response remains to be explored. In this study, we show that inhibition of Wnt/β-catenin signaling reduces inflammation and mitigates sepsis-induced organ injury. Using in vitro LPS-stimulated RAW264.7 macrophages, we demonstrate that a small-molecule inhibitor of β-catenin responsive transcription, iCRT3, significantly reduces the LPS-induced Wnt/β-catenin activity and also inhibits TNF-α production and IκB degradation in a dose-dependent manner. Intraperitoneal administration of iCRT3 to C57BL/6 mice, subjected to cecal ligation and puncture-induced sepsis, decreases the plasma levels of proinflammatory cytokines and organ injury markers in a dose-dependent manner. The histological integrity of the lungs is improved with iCRT3 treatment, along with reduced lung collagen deposition and apoptosis. In addition, iCRT3 treatment also decreases the expression of the cytokines, neutrophil chemoattractants, as well as the MPO activity in the lungs of septic mice. Based on these findings we conclude that targeting the Wnt/β-Catenin pathway may provide a potential therapeutic approach for treatment of sepsis.Archna SharmaWeng-Lang YangMahendar OchaniPing WangNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-14 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Archna Sharma Weng-Lang Yang Mahendar Ochani Ping Wang Mitigation of sepsis-induced inflammatory responses and organ injury through targeting Wnt/β-catenin signaling
description	Abstract The Wnt/β-catenin pathway has been involved in regulating inflammation in various infectious and inflammatory diseases. Sepsis is a life-threatening condition caused by dysregulated inflammatory response to infection with no effective therapy available. Recently elevated Wnt/β-catenin signaling has been detected in sepsis. However, its contribution to sepsis-associated inflammatory response remains to be explored. In this study, we show that inhibition of Wnt/β-catenin signaling reduces inflammation and mitigates sepsis-induced organ injury. Using in vitro LPS-stimulated RAW264.7 macrophages, we demonstrate that a small-molecule inhibitor of β-catenin responsive transcription, iCRT3, significantly reduces the LPS-induced Wnt/β-catenin activity and also inhibits TNF-α production and IκB degradation in a dose-dependent manner. Intraperitoneal administration of iCRT3 to C57BL/6 mice, subjected to cecal ligation and puncture-induced sepsis, decreases the plasma levels of proinflammatory cytokines and organ injury markers in a dose-dependent manner. The histological integrity of the lungs is improved with iCRT3 treatment, along with reduced lung collagen deposition and apoptosis. In addition, iCRT3 treatment also decreases the expression of the cytokines, neutrophil chemoattractants, as well as the MPO activity in the lungs of septic mice. Based on these findings we conclude that targeting the Wnt/β-Catenin pathway may provide a potential therapeutic approach for treatment of sepsis.
format	article
author	Archna Sharma Weng-Lang Yang Mahendar Ochani Ping Wang
author_facet	Archna Sharma Weng-Lang Yang Mahendar Ochani Ping Wang
author_sort	Archna Sharma
title	Mitigation of sepsis-induced inflammatory responses and organ injury through targeting Wnt/β-catenin signaling
title_short	Mitigation of sepsis-induced inflammatory responses and organ injury through targeting Wnt/β-catenin signaling
title_full	Mitigation of sepsis-induced inflammatory responses and organ injury through targeting Wnt/β-catenin signaling
title_fullStr	Mitigation of sepsis-induced inflammatory responses and organ injury through targeting Wnt/β-catenin signaling
title_full_unstemmed	Mitigation of sepsis-induced inflammatory responses and organ injury through targeting Wnt/β-catenin signaling
title_sort	mitigation of sepsis-induced inflammatory responses and organ injury through targeting wnt/β-catenin signaling
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/adcd7b62b5484633bddd183d38ff0f76
work_keys_str_mv	AT archnasharma mitigationofsepsisinducedinflammatoryresponsesandorganinjurythroughtargetingwntbcateninsignaling AT wenglangyang mitigationofsepsisinducedinflammatoryresponsesandorganinjurythroughtargetingwntbcateninsignaling AT mahendarochani mitigationofsepsisinducedinflammatoryresponsesandorganinjurythroughtargetingwntbcateninsignaling AT pingwang mitigationofsepsisinducedinflammatoryresponsesandorganinjurythroughtargetingwntbcateninsignaling
_version_	1718384679267074048

Mitigation of sepsis-induced inflammatory responses and organ injury through targeting Wnt/β-catenin signaling

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