Endocytic pathways regulate Toll-like receptor 4 signaling and link innate and adaptive immunity

Husebye, Harald; Halaas, Øyvind; Stenmark, Harald; Tunheim, Gro; Sandanger, Øystein; Bogen, Bjarne; Brech, Andreas; Latz, Eicke; Espevik, Terje

doi:10.1038/sj.emboj.7600991

Cited by 417 publications

(470 citation statements)

References 54 publications

(87 reference statements)

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“…The effect of C-peptide that we observed on the nuclear factor kappaB (NF-κB) pathway in both HAEC and UASMC [13,15] might thus originate from C-peptidereceptor complex signalling from the endosomes, as has been demonstrated for certain Toll-like receptor pathways and other inflammatory pathways, which affect the activation of the NF-κB pathway from the endosomes [34,35]. The mildly acidic pH of the sorting endosomes would then begin the dissociation of the C-peptide destined to lysosomes from its recycled receptor.…”

Section: Discussionmentioning

confidence: 56%

C-peptide is internalised in human endothelial and vascular smooth muscle cells via early endosomes

et al. 2009

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Aims/hypothesis There is increasing evidence that Cpeptide exerts intracellular effects in a variety of cells and could be beneficial in patients with type 1 diabetes. Exactly how C-peptide achieves these effects, however, is unknown. Recent reports showed that C-peptide internalised in the cytoplasm of HEK-293 and Swiss 3T3 cells, where it was not degraded for at least 1 h after uptake. In this study, we investigated the hypothesis that C-peptide is internalised via an endocytic pathway and traffics to classic endocytic organelles, such as endosomes and lysosomes. Methods We studied the internalisation of C-peptide in vascular endothelial and smooth muscle cells, two relevant targets of Cpeptide activity, by using Alexa Fluor-labelled C-peptide probes in living cells and immunohistochemistry employing confocal laser-scanning microscopy. To examine trafficking to subcellular compartments, we used fluorescent constructs tagged to RAB5A, member RAS oncogene family (RAB5A) to identify early endosomes, or to lysosomal-associated membrane protein 1 (LAMP1) to identify lysosomes.Results C-peptide internalised in the cytoplasm of cells within punctate structures identified as early endosomes. Internalisation was clearly detectable after 10 min of incubation and was blocked at 4°C as well as with excess of unlabelled C-peptide. A minor fraction of vesicles, which increased with culture time, co-localised with lysosomes. Uptake of C-peptide was reduced by monodansylcadaverine, a pharmacological compound that blocks clathrin-mediated endocytosis, and by nocodazole, which disrupts microtubule assembly. Conclusions/interpretation C-peptide internalises in the cytoplasm of cells by endocytosis, as demonstrated by its localisation in early endosomes. Endosomes might represent a signalling station, through which C-peptide might achieve its cellular effects.

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Section: Discussionmentioning

confidence: 56%

C-peptide is internalised in human endothelial and vascular smooth muscle cells via early endosomes

et al. 2009

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“…Thus, morphine-induced proinflammatory glial activation via TLR4 could potentially provide an explanation for tolerance to the analgesic effects of morphine. The TLR4 agonist, LPS, can induce endosomal trafficking of TLR4 leading to lysosomal degradation and signal termination [13]. However, it is unknown how morphine induces proinflammatory microglial activation and IL-1β release via TLR4.…”

Section: Introductionmentioning

confidence: 99%

Morphine enhances IL-1β release through toll-like receptor 4-mediated endocytic pathway in microglia

Liang

Jiang

et al. 2016

Purinergic Signalling

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Morphine creates a neuroinflammatory response and enhances release of the proinflammatory cytokines like interleukin-1β (IL-1β), which compromises morphine analgesia as well as induces morphine tolerance. In this study, we attempted to investigate the mechanisms of morphine induced IL-1β synthesis and release. Microglial cells were treated with morphine (100 μM) once daily for 3 days. Control groups underwent the same procedure but received sterile saline injection instead of morphine. Toll-like receptor 4 (TLR4) and P2X4 receptor (P2X4R) signaling were analyzed using Western blot; immunofluorescence was used to detect the signaling of CD68; real-time RT-PCR and ELISA kit was used to measure the messenger RNA and protein synthesis and release level of IL-1β. Morphine enhanced IL-1β synthesis and P2X4R protein expression. TLR4 were responsible for morphine-induced IL-1β synthesis, while morphineinduced IL-1β release was via P2X4R. Morphineinduced IL-1β release is mediated by endocytosis of TLR4. These results indicated that TLR4 and P2X4R pathways mediated IL-1β synthesis and release in microglia followed chronic morphine. TLR4 internalization is the main mechanism of morphine-induced microglia activation and IL-1β release.

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“…18,19 Mechanisms of TLR4 internalization can include association with endocytosis proteins such as clathrin, dynamin, and caveolin-1. 20,21 Caveolin-1 is a transmembranescaffolding protein, and the major structural component of caveolae that contribute to many cell functions including endocytosis, potocytosis, transcytosis, as well as calcium signaling. 21 Caveolin-1-mediated internalization of multiple cell surface receptors is also known to critically regulate receptor signaling.…”

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confidence: 99%

Tissue damage negatively regulates LPS-induced macrophage necroptosis

Scott

Fan

et al. 2016

Cell Death Differ

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Infection is a common clinical complication following tissue damage resulting from surgery and severe trauma. Studies have suggested that cell pre-activation by antecedent trauma/tissue damage profoundly impacts the response of innate immune cells to a secondary infectious stimulus. Cell necroptosis, a form of regulated inflammatory cell death, is one of the mechanisms that control cell release of inflammatory mediators from important innate immune executive cells such as macrophages (Mϕ), which critically regulate the progress of inflammation. In this study, we investigated the mechanism and role of trauma/tissue damage in the regulation of LPS-induced Mϕ necroptosis using a mouse model simulating long-bone fracture. We demonstrate that LPS acting through Toll-like receptor (TLR) 4 promotes Mϕ necroptosis. However, necroptosis is ameliorated by high-mobility group box 1 (HMGB1) release from damaged tissue. We show that HMGB1 acting through cell surface receptor for advanced glycation end products (RAGE) upregulates caveolin-1 expression, which in turn induces caveolae-mediated TLR4 internalization and desensitization to decrease Mϕ necroptosis. We further show that RAGE-MyD88 activation of Cdc42 and subsequent activation of transcription factor Sp1 serves as a mechanism underlying caveolin-1 transcriptional upregulation. These results reveal a previous unidentified protective role of damage-associated molecular pattern (DAMP) molecules in restricting inflammation in response to exogenous pathogen-associated molecular pattern molecules.

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Endocytic pathways regulate Toll-like receptor 4 signaling and link innate and adaptive immunity

Cited by 417 publications

References 54 publications

C-peptide is internalised in human endothelial and vascular smooth muscle cells via early endosomes

C-peptide is internalised in human endothelial and vascular smooth muscle cells via early endosomes

Morphine enhances IL-1β release through toll-like receptor 4-mediated endocytic pathway in microglia

Tissue damage negatively regulates LPS-induced macrophage necroptosis

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