Interaction of Opioids with TLR4—Mechanisms and Ramifications

The innate immune receptor toll-like receptor 4 (TLR4) is known as a sensor for the gram-negative bacterial cell wall component lipopolysaccharide (LPS). TLR4 activation leads to a strong pro-inflammatory response in macrophages; however, it is also recognised to play a key role in cancer. Recent st...

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Autores principales:	Mai Mahmoud Gabr, Iqira Saeed, Jared A. Miles, Benjamin P. Ross, Paul Nicholas Shaw, Markus W. Hollmann, Marie-Odile Parat
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	toll-like receptor 4 morphine opioids lipopolysaccharide Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/143acb6bbf5b4985a371157f0e1aa57e
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spelling	oai:doaj.org-article:143acb6bbf5b4985a371157f0e1aa57e2021-11-11T15:26:57ZInteraction of Opioids with TLR4—Mechanisms and Ramifications10.3390/cancers132152742072-6694https://doaj.org/article/143acb6bbf5b4985a371157f0e1aa57e2021-10-01T00:00:00Zhttps://www.mdpi.com/2072-6694/13/21/5274https://doaj.org/toc/2072-6694The innate immune receptor toll-like receptor 4 (TLR4) is known as a sensor for the gram-negative bacterial cell wall component lipopolysaccharide (LPS). TLR4 activation leads to a strong pro-inflammatory response in macrophages; however, it is also recognised to play a key role in cancer. Recent studies of the opioid receptor (OR)-independent actions of opioids have identified that TLR4 can respond to opioids. Opioids are reported to weakly activate TLR4, but to significantly inhibit LPS-induced TLR4 activation. The action of opioids at TLR4 is suggested to be non-stereoselective, this is because OR-inactive (+)-isomers of opioids have been shown to activate or to inhibit TLR4 signalling, although there is some controversy in the literature. While some opioids can bind to the lipopolysaccharide (LPS)-binding cleft of the Myeloid Differentiation factor 2 (MD-2) co-receptor, pharmacological characterisation of the inhibition of opioids on LPS activation of TLR4 indicates a noncompetitive mechanism. In addition to a direct interaction at the receptor, opioids affect NF-κB activation downstream of both TLR4 and opioid receptors and modulate TLR4 expression, leading to a range of in vivo outcomes. Here, we review the literature reporting the activity of opioids at TLR4, its proposed mechanism(s), and the complex functional consequences of this interaction.Mai Mahmoud GabrIqira SaeedJared A. MilesBenjamin P. RossPaul Nicholas ShawMarkus W. HollmannMarie-Odile ParatMDPI AGarticletoll-like receptor 4morphineopioidslipopolysaccharideNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENCancers, Vol 13, Iss 5274, p 5274 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	toll-like receptor 4 morphine opioids lipopolysaccharide Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	toll-like receptor 4 morphine opioids lipopolysaccharide Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Mai Mahmoud Gabr Iqira Saeed Jared A. Miles Benjamin P. Ross Paul Nicholas Shaw Markus W. Hollmann Marie-Odile Parat Interaction of Opioids with TLR4—Mechanisms and Ramifications
description	The innate immune receptor toll-like receptor 4 (TLR4) is known as a sensor for the gram-negative bacterial cell wall component lipopolysaccharide (LPS). TLR4 activation leads to a strong pro-inflammatory response in macrophages; however, it is also recognised to play a key role in cancer. Recent studies of the opioid receptor (OR)-independent actions of opioids have identified that TLR4 can respond to opioids. Opioids are reported to weakly activate TLR4, but to significantly inhibit LPS-induced TLR4 activation. The action of opioids at TLR4 is suggested to be non-stereoselective, this is because OR-inactive (+)-isomers of opioids have been shown to activate or to inhibit TLR4 signalling, although there is some controversy in the literature. While some opioids can bind to the lipopolysaccharide (LPS)-binding cleft of the Myeloid Differentiation factor 2 (MD-2) co-receptor, pharmacological characterisation of the inhibition of opioids on LPS activation of TLR4 indicates a noncompetitive mechanism. In addition to a direct interaction at the receptor, opioids affect NF-κB activation downstream of both TLR4 and opioid receptors and modulate TLR4 expression, leading to a range of in vivo outcomes. Here, we review the literature reporting the activity of opioids at TLR4, its proposed mechanism(s), and the complex functional consequences of this interaction.
format	article
author	Mai Mahmoud Gabr Iqira Saeed Jared A. Miles Benjamin P. Ross Paul Nicholas Shaw Markus W. Hollmann Marie-Odile Parat
author_facet	Mai Mahmoud Gabr Iqira Saeed Jared A. Miles Benjamin P. Ross Paul Nicholas Shaw Markus W. Hollmann Marie-Odile Parat
author_sort	Mai Mahmoud Gabr
title	Interaction of Opioids with TLR4—Mechanisms and Ramifications
title_short	Interaction of Opioids with TLR4—Mechanisms and Ramifications
title_full	Interaction of Opioids with TLR4—Mechanisms and Ramifications
title_fullStr	Interaction of Opioids with TLR4—Mechanisms and Ramifications
title_full_unstemmed	Interaction of Opioids with TLR4—Mechanisms and Ramifications
title_sort	interaction of opioids with tlr4—mechanisms and ramifications
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/143acb6bbf5b4985a371157f0e1aa57e
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Interaction of Opioids with TLR4—Mechanisms and Ramifications

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