S1P/S1P<sub>2</sub> Signaling Axis Regulates Both NLRP3 Upregulation and NLRP3 Inflammasome Activation in Macrophages Primed with Lipopolysaccharide

The activation of NLRP3 inflammasome is a key factor for various inflammatory diseases. Here, we provide experimental evidence supporting the regulatory role of sphingosine-1-phosphate (S1P) in NLRP3 inflammasome activation in mouse bone-marrow-derived macrophages (BMDMs), along with the S1P recepto...

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Autores principales:	Chi-Ho Lee, Ji Woong Choi
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	S1P S1P<sub>2</sub> LPS bone marrow-derived macrophage NLRP3 upregulation NLRP3 inflammasome activation Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/7e20c0f07dec4bf4ac2bcc30dcb53a7e
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spelling	oai:doaj.org-article:7e20c0f07dec4bf4ac2bcc30dcb53a7e2021-11-25T16:26:43ZS1P/S1P<sub>2</sub> Signaling Axis Regulates Both NLRP3 Upregulation and NLRP3 Inflammasome Activation in Macrophages Primed with Lipopolysaccharide10.3390/antiox101117062076-3921https://doaj.org/article/7e20c0f07dec4bf4ac2bcc30dcb53a7e2021-10-01T00:00:00Zhttps://www.mdpi.com/2076-3921/10/11/1706https://doaj.org/toc/2076-3921The activation of NLRP3 inflammasome is a key factor for various inflammatory diseases. Here, we provide experimental evidence supporting the regulatory role of sphingosine-1-phosphate (S1P) in NLRP3 inflammasome activation in mouse bone-marrow-derived macrophages (BMDMs), along with the S1P receptor subtype involved and underlying regulatory mechanisms. During the priming stage, S1P induced NLRP3 upregulation in BMDMs only when primed with lipopolysaccharide (LPS). In this event, S1P<sub>2</sub>, but not S1P<sub>1</sub>, was involved based on the attenuated NLRP3 upregulation with JTE013 (S1P<sub>2</sub> antagonist) or S1P<sub>2</sub> knockdown. During the activation stage, S1P induced NLRP3 inflammasome activation in LPS-primed BMDMs via caspase-1 activation, interleukin 1β maturation, apoptosis-associated speck-like protein containing a CARD (ASC) speck formation, and IL-1β secretion. Such NLRP3 inflammasome activation was blocked by either pharmacological inhibition or genetic knockdown of S1P<sub>2</sub>. NF-κB, PI3K/Akt, and ERK1/2 were identified as effector pathways underlying S1P/S1P<sub>2</sub> signaling in the regulation of NLRP3 upregulation in LPS-primed BMDMs. Further, reactive oxygen species (ROS) production was dependent on the S1P/S1P<sub>2</sub> signaling axis in these cells, and the ROS generated regulate NLRP3 inflammasome activation, but not NLRP3 priming. Collectively, our findings suggest that S1P promotes NLRP3 upregulation and NLRP3 inflammasome activation in LPS-primed BMDMs via S1P<sub>2</sub> and subsequent effector pathways.Chi-Ho LeeJi Woong ChoiMDPI AGarticleS1PS1P<sub>2</sub>LPSbone marrow-derived macrophageNLRP3 upregulationNLRP3 inflammasome activationTherapeutics. PharmacologyRM1-950ENAntioxidants, Vol 10, Iss 1706, p 1706 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	S1P S1P<sub>2</sub> LPS bone marrow-derived macrophage NLRP3 upregulation NLRP3 inflammasome activation Therapeutics. Pharmacology RM1-950
spellingShingle	S1P S1P<sub>2</sub> LPS bone marrow-derived macrophage NLRP3 upregulation NLRP3 inflammasome activation Therapeutics. Pharmacology RM1-950 Chi-Ho Lee Ji Woong Choi S1P/S1P<sub>2</sub> Signaling Axis Regulates Both NLRP3 Upregulation and NLRP3 Inflammasome Activation in Macrophages Primed with Lipopolysaccharide
description	The activation of NLRP3 inflammasome is a key factor for various inflammatory diseases. Here, we provide experimental evidence supporting the regulatory role of sphingosine-1-phosphate (S1P) in NLRP3 inflammasome activation in mouse bone-marrow-derived macrophages (BMDMs), along with the S1P receptor subtype involved and underlying regulatory mechanisms. During the priming stage, S1P induced NLRP3 upregulation in BMDMs only when primed with lipopolysaccharide (LPS). In this event, S1P<sub>2</sub>, but not S1P<sub>1</sub>, was involved based on the attenuated NLRP3 upregulation with JTE013 (S1P<sub>2</sub> antagonist) or S1P<sub>2</sub> knockdown. During the activation stage, S1P induced NLRP3 inflammasome activation in LPS-primed BMDMs via caspase-1 activation, interleukin 1β maturation, apoptosis-associated speck-like protein containing a CARD (ASC) speck formation, and IL-1β secretion. Such NLRP3 inflammasome activation was blocked by either pharmacological inhibition or genetic knockdown of S1P<sub>2</sub>. NF-κB, PI3K/Akt, and ERK1/2 were identified as effector pathways underlying S1P/S1P<sub>2</sub> signaling in the regulation of NLRP3 upregulation in LPS-primed BMDMs. Further, reactive oxygen species (ROS) production was dependent on the S1P/S1P<sub>2</sub> signaling axis in these cells, and the ROS generated regulate NLRP3 inflammasome activation, but not NLRP3 priming. Collectively, our findings suggest that S1P promotes NLRP3 upregulation and NLRP3 inflammasome activation in LPS-primed BMDMs via S1P<sub>2</sub> and subsequent effector pathways.
format	article
author	Chi-Ho Lee Ji Woong Choi
author_facet	Chi-Ho Lee Ji Woong Choi
author_sort	Chi-Ho Lee
title	S1P/S1P<sub>2</sub> Signaling Axis Regulates Both NLRP3 Upregulation and NLRP3 Inflammasome Activation in Macrophages Primed with Lipopolysaccharide
title_short	S1P/S1P<sub>2</sub> Signaling Axis Regulates Both NLRP3 Upregulation and NLRP3 Inflammasome Activation in Macrophages Primed with Lipopolysaccharide
title_full	S1P/S1P<sub>2</sub> Signaling Axis Regulates Both NLRP3 Upregulation and NLRP3 Inflammasome Activation in Macrophages Primed with Lipopolysaccharide
title_fullStr	S1P/S1P<sub>2</sub> Signaling Axis Regulates Both NLRP3 Upregulation and NLRP3 Inflammasome Activation in Macrophages Primed with Lipopolysaccharide
title_full_unstemmed	S1P/S1P<sub>2</sub> Signaling Axis Regulates Both NLRP3 Upregulation and NLRP3 Inflammasome Activation in Macrophages Primed with Lipopolysaccharide
title_sort	s1p/s1p<sub>2</sub> signaling axis regulates both nlrp3 upregulation and nlrp3 inflammasome activation in macrophages primed with lipopolysaccharide
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/7e20c0f07dec4bf4ac2bcc30dcb53a7e
work_keys_str_mv	AT chiholee s1ps1psub2subsignalingaxisregulatesbothnlrp3upregulationandnlrp3inflammasomeactivationinmacrophagesprimedwithlipopolysaccharide AT jiwoongchoi s1ps1psub2subsignalingaxisregulatesbothnlrp3upregulationandnlrp3inflammasomeactivationinmacrophagesprimedwithlipopolysaccharide
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S1P/S1P<sub>2</sub> Signaling Axis Regulates Both NLRP3 Upregulation and NLRP3 Inflammasome Activation in Macrophages Primed with Lipopolysaccharide

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