Abstract
Simple SummaryRecent evidence indicates that opioids can be active at a receptor that is abundantly expressed on innate immune cells as well as cancer cells: the receptor is termed toll-like receptor 4 (TLR4). TLR4 is increasingly recognised as playing key roles in tumour biology and anticancer defences. However, the issue of whether TLR4 mediates some of the effects of opioids on tumour growth and metastasis is entirely unknown. We review existing evidence, mechanisms, and functional consequences of the action of opioids at TLR4. This opens new avenues of research on the role of opioids in cancer.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.
Highlights
Toll-like receptors (TLRs) are a family of pattern recognition receptors first identified in Drosophila, and to date, ten members of the TLR family are recognised in humans [1].One of the most widely studied TLRs is toll-like receptor 4 (TLR4), a membrane-bound receptor that has an extracellular leucine-rich repeat domain, a transmembrane domain, and a cytoplasmic toll/interleukin-1 receptor (TIR) domain [2]
The discrepancies in the effect of TLR4 ablation on morphine pharmacodynamics have been proposed to be due to confounders in studies, e.g., higher morphine-induced analgesia in TLR4-knockout animals compared with the control strain, the effect of opioid binding to MD2 in absence of TLR4, and the concentration of opioids to which receptors are exposed in vivo [130,131]
Morphine was shown to disrupt the tight junction protein organisation between intestinal epithelial cells. This effect was significantly attenuated in TLR4−/− mice and completely abolished in mice lacking μ-opioid receptor, and in TLR2−/− and TLR2/4−/− double knockout mice, which implies that disruption of intestinal barrier function by morphine is partially mediated by TLR4
Summary
Toll-like receptors (TLRs) are a family of pattern recognition receptors first identified in Drosophila, and to date, ten members of the TLR family are recognised in humans [1]. The activation of TLR4 by natural ligand lipopolysaccharide (LPS)—a PAMP contained in gram-negative bacteria cell membranes—requires the involvement of the Cancers 2021, 13, 5274 of danger [3]. TLR4 isincreasingly increasinglyrecognized recognized playing important in cancer It is abundantly expressed on tumoural immune and non-immune stromal cells and is often [7,8]). DAMPs expressed by cancer cells can promote angiogenesis [16]. A major endogenous and DAMPs expressed by cancer cells can promote angiogenesis [16]. HMGB1 produced by tumour cells interacts with TLR4 on platelets, causing their activation, adhethat is produced by tumour cells interacts with TLR4 on platelets, causing their activation, sion, and release of pro-metastatic factors, resulting in metastasis in mice [17]. Mechanisms, and functional consequences of the action of opioids at TLR4
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