Targeting TBK1 Attenuates LPS-Induced NLRP3 Inflammasome Activation by Regulating of mTORC1 Pathways in Trophoblasts

Pathological maternal inflammation and abnormal placentation contribute to several pregnancy-related disorders, including preterm birth, intrauterine growth restriction, and preeclampsia. TANK-binding kinase 1 (TBK1), a serine/threonine kinase, has been implicated in the regulation of various physio...

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Autores principales:	Sohee Lee, Jiha Shin, Jong-Seok Kim, Jongdae Shin, Sung Ki Lee, Hwan-Woo Park
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	TBK1 NLRP3 inflammasome maternal inflammation trophoblast placenta mTORC1 Immunologic diseases. Allergy RC581-607
Acceso en línea:	https://doaj.org/article/b05804b2a6a74dd6a1c36fa320f25701
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spelling	oai:doaj.org-article:b05804b2a6a74dd6a1c36fa320f257012021-11-09T06:17:30ZTargeting TBK1 Attenuates LPS-Induced NLRP3 Inflammasome Activation by Regulating of mTORC1 Pathways in Trophoblasts1664-322410.3389/fimmu.2021.743700https://doaj.org/article/b05804b2a6a74dd6a1c36fa320f257012021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fimmu.2021.743700/fullhttps://doaj.org/toc/1664-3224Pathological maternal inflammation and abnormal placentation contribute to several pregnancy-related disorders, including preterm birth, intrauterine growth restriction, and preeclampsia. TANK-binding kinase 1 (TBK1), a serine/threonine kinase, has been implicated in the regulation of various physiological processes, including innate immune response, autophagy, and cell growth. However, the relevance of TBK1 in the placental pro-inflammatory environment has not been investigated. In this study, we assessed the effect of TBK1 inhibition on lipopolysaccharide (LPS)-induced NLRP3 inflammasome activation and its underlying mechanisms in human trophoblast cell lines and mouse placenta. TBK1 phosphorylation was upregulated in the trophoblasts and placenta in response to LPS. Pharmacological and genetic inhibition of TBK1 in trophoblasts ameliorated LPS-induced NLRP3 inflammasome activation, placental inflammation, and subsequent interleukin (IL)-1 production. Moreover, maternal administration of amlexanox, a TBK1 inhibitor, reversed LPS-induced adverse pregnancy outcomes. Notably, TBK1 inhibition prevented LPS-induced NLRP3 inflammasome activation by targeting the mammalian target of rapamycin complex 1 (mTORC1). Thus, this study provides evidence for the biological significance of TBK1 in placental inflammation, suggesting that amlexanox may be a potential therapeutic candidate for treating inflammation-associated pregnancy-related complications.Sohee LeeJiha ShinJong-Seok KimJongdae ShinJongdae ShinSung Ki LeeSung Ki LeeHwan-Woo ParkFrontiers Media S.A.articleTBK1NLRP3 inflammasomematernal inflammationtrophoblastplacentamTORC1Immunologic diseases. AllergyRC581-607ENFrontiers in Immunology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	TBK1 NLRP3 inflammasome maternal inflammation trophoblast placenta mTORC1 Immunologic diseases. Allergy RC581-607
spellingShingle	TBK1 NLRP3 inflammasome maternal inflammation trophoblast placenta mTORC1 Immunologic diseases. Allergy RC581-607 Sohee Lee Jiha Shin Jong-Seok Kim Jongdae Shin Jongdae Shin Sung Ki Lee Sung Ki Lee Hwan-Woo Park Targeting TBK1 Attenuates LPS-Induced NLRP3 Inflammasome Activation by Regulating of mTORC1 Pathways in Trophoblasts
description	Pathological maternal inflammation and abnormal placentation contribute to several pregnancy-related disorders, including preterm birth, intrauterine growth restriction, and preeclampsia. TANK-binding kinase 1 (TBK1), a serine/threonine kinase, has been implicated in the regulation of various physiological processes, including innate immune response, autophagy, and cell growth. However, the relevance of TBK1 in the placental pro-inflammatory environment has not been investigated. In this study, we assessed the effect of TBK1 inhibition on lipopolysaccharide (LPS)-induced NLRP3 inflammasome activation and its underlying mechanisms in human trophoblast cell lines and mouse placenta. TBK1 phosphorylation was upregulated in the trophoblasts and placenta in response to LPS. Pharmacological and genetic inhibition of TBK1 in trophoblasts ameliorated LPS-induced NLRP3 inflammasome activation, placental inflammation, and subsequent interleukin (IL)-1 production. Moreover, maternal administration of amlexanox, a TBK1 inhibitor, reversed LPS-induced adverse pregnancy outcomes. Notably, TBK1 inhibition prevented LPS-induced NLRP3 inflammasome activation by targeting the mammalian target of rapamycin complex 1 (mTORC1). Thus, this study provides evidence for the biological significance of TBK1 in placental inflammation, suggesting that amlexanox may be a potential therapeutic candidate for treating inflammation-associated pregnancy-related complications.
format	article
author	Sohee Lee Jiha Shin Jong-Seok Kim Jongdae Shin Jongdae Shin Sung Ki Lee Sung Ki Lee Hwan-Woo Park
author_facet	Sohee Lee Jiha Shin Jong-Seok Kim Jongdae Shin Jongdae Shin Sung Ki Lee Sung Ki Lee Hwan-Woo Park
author_sort	Sohee Lee
title	Targeting TBK1 Attenuates LPS-Induced NLRP3 Inflammasome Activation by Regulating of mTORC1 Pathways in Trophoblasts
title_short	Targeting TBK1 Attenuates LPS-Induced NLRP3 Inflammasome Activation by Regulating of mTORC1 Pathways in Trophoblasts
title_full	Targeting TBK1 Attenuates LPS-Induced NLRP3 Inflammasome Activation by Regulating of mTORC1 Pathways in Trophoblasts
title_fullStr	Targeting TBK1 Attenuates LPS-Induced NLRP3 Inflammasome Activation by Regulating of mTORC1 Pathways in Trophoblasts
title_full_unstemmed	Targeting TBK1 Attenuates LPS-Induced NLRP3 Inflammasome Activation by Regulating of mTORC1 Pathways in Trophoblasts
title_sort	targeting tbk1 attenuates lps-induced nlrp3 inflammasome activation by regulating of mtorc1 pathways in trophoblasts
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/b05804b2a6a74dd6a1c36fa320f25701
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Targeting TBK1 Attenuates LPS-Induced NLRP3 Inflammasome Activation by Regulating of mTORC1 Pathways in Trophoblasts

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