p(HGNC:TLR4)
NFT containing neurons upregulated genes involved in cell survival and viability, inflammation, cell cycle progression and molecular transport and downregulated apoptosis, necrosis and cell death pathways (Figure 1a). NFkB, a pro-survival master transcriptional regulator of inflammation, was the highest predicted upstream regulator of the NFT-gene expression profile. In agreement with inflammatory activation, other predicted upstream regulators included IFNG, TNF, TLR4, IL1B and CXCL1 (Figure 1b) PubMed:30126037
Pattern recognition receptors such as the TLR4 receptor are expressed in the brain’s own immune cells like microglia and astrocytes that induce inflammation via cytokine secretion [38]. PubMed:27314526
Pattern recognition receptors such as the TLR4 receptor are expressed in the brain’s own immune cells like microglia and astrocytes that induce inflammation via cytokine secretion [38]. PubMed:27314526
Pretreatment with genistein significantly alleviated A 25-35-stimulated TLR4 and NF-B expres-sion, DNA binding and NF-B activities[159]. PubMed:29179999
The expression of the protein and mRNA of TLR3, TLR4, NF-B and TNF receptor associated factor 6 (TRAF-6) were substantially decreased by ginsenoside Rg1, and it also decreased the expression of TNF- and IFN- [227] PubMed:29179999
The TLR4 activates two distinct pathways: MyD88 and TRIF. In macrophages, heme induces a biased MyD88 activation and the secretion of the pro-inflammatory cytokines TNF and KC. PubMed:24904418
Moreover, human embryonic kidney (HEK) cells transfected with human TLR4 secretes IL-8 upon stimulation with heme (Piazza et al., 2011). PubMed:24904418
Heme amplifies cytokines induced by cell surface receptors (TLR2, TLR4, TLR5), endosome receptors (TLR3, TLR9), and cytosolic receptors (NOD1 and NOD2). PubMed:24904418
In fact, TLR4 is involved in intracerebral hemorrhage (ICH) induced by heme (Lin et al., 2012). PubMed:24904418
Other studies demonstrated that heme can trigger the activation of Toll-like receptor 4 and inflammasomes, thus leading to inflammatory reactions.5,35–37 PubMed:26794659
Most studies concerning the pathophysiological roles of heme have focused on the protective effect of the heme-degrading enzyme, heme oxygenase 1 (HO-1) [25] (Box 2), and on the effect of this danger-associated molecule on cells, leading to oxidative stress, TLR4 signaling [26,27], and NLRP3 inflammasome activation [28] (Box 4). PubMed:26875449
Cell-free heme selectively triggers pro-inflammatory receptors such as TLR-4 and BACH-1, and activates proteasomes25. PubMed:27515135
Purified heme was found to be an activator of TLR4 8,11,27 in some studies and of the inflammasome 9 in others, and these activities were considered to be the molecular mechanism behind the coexistence of inflammation and hemolysis. PubMed:29610666
Only under protein-free conditions did we observe a limited heme-induced TNF-alpha response in cultured macrophages, which was triggered via signaling of the classical TLR4–MyD88–TRIF pathway of NF-kB activation.28 PubMed:29610666
The released heme can activate the innate immune pattern recognition receptor toll-like receptor 4 (TLR4) on inflammatory cells, platelets and endothelium, promoting a pro-inflammatory and pro-coagulant phenotype, ultimately leading to vaso-occlusion, ischemia-reperfusion physiology, tissue injury, and pain in murine models of SCD [5, 7±10]. PubMed:29694434
Heme released from cell-free hemoglobin has been described to be an activator of TLR-4 [39, 41, 42]. PubMed:29956069
Heme/TLR-4 signaling, moreover, was found to activate NF-κB and trigger vaso-occlusion [42]. PubMed:29956069
In mice, this response was attenuated after administration of the TLR-4 inhibitor, TAK-242, suggesting hemin potentiates pulmonary macrophage activation and inflammation through hemin-induced TLR-4 receptor binding [27]. PubMed:30281034
The cause of sepsis is primarily an exaggerated, generalized inflammatory response to an extrinsic stimulus. Mechanistically, so-called PAMPs (pathogen-associated molecular patterns) lead to the activation of pattern recognition receptors (PRRs) such as tolllike receptors (TLRs) and C-type lectin receptors (CLRs) [28, 29]. PubMed:29956069
In recent years, it has also been shown that toll-like receptors and other pattern recognition receptors are activated not only by extrinsic factors but also by intrinsic stimuli (so called damage-associated molecular patterns, DAMPs) that are released when the host cell is damaged [27, 29]. PubMed:29956069
Other studies demonstrated that heme can trigger the activation of Toll-like receptor 4 and inflammasomes, thus leading to inflammatory reactions.5,35–37 PubMed:26794659
The released heme can activate the innate immune pattern recognition receptor toll-like receptor 4 (TLR4) on inflammatory cells, platelets and endothelium, promoting a pro-inflammatory and pro-coagulant phenotype, ultimately leading to vaso-occlusion, ischemia-reperfusion physiology, tissue injury, and pain in murine models of SCD [5, 7±10]. PubMed:29694434
In fact, Tlr4-/- or anti-TLR4 treatment suppresses heme-induced neuroinflammation, edema, and neurologic deficit. PubMed:24904418
In fact, Tlr4-/- or anti-TLR4 treatment suppresses heme-induced neuroinflammation, edema, and neurologic deficit. PubMed:24904418
Pattern recognition receptors such as the TLR4 receptor are expressed in the brain’s own immune cells like microglia and astrocytes that induce inflammation via cytokine secretion [38]. PubMed:27314526
Moreover, human embryonic kidney (HEK) cells transfected with human TLR4 secretes IL-8 upon stimulation with heme (Piazza et al., 2011). PubMed:24904418
The TLR4 activates two distinct pathways: MyD88 and TRIF. In macrophages, heme induces a biased MyD88 activation and the secretion of the pro-inflammatory cytokines TNF and KC. PubMed:24904418
Only under protein-free conditions did we observe a limited heme-induced TNF-alpha response in cultured macrophages, which was triggered via signaling of the classical TLR4–MyD88–TRIF pathway of NF-kB activation.28 PubMed:29610666
The TLR4 activates two distinct pathways: MyD88 and TRIF. In macrophages, heme induces a biased MyD88 activation and the secretion of the pro-inflammatory cytokines TNF and KC. PubMed:24904418
Only under protein-free conditions did we observe a limited heme-induced TNF-alpha response in cultured macrophages, which was triggered via signaling of the classical TLR4–MyD88–TRIF pathway of NF-kB activation.28 PubMed:29610666
TLR4 activation leads to MAPKs and NFκB activation, which are necessary to TNF secretion. PubMed:24904418
TLR4 activation leads to MAPKs and NFκB activation, which are necessary to TNF secretion. PubMed:24904418
In fact, Tlr4-/- or anti-TLR4 treatment suppresses heme-induced neuroinflammation, edema, and neurologic deficit. PubMed:24904418
In fact, Tlr4-/- or anti-TLR4 treatment suppresses heme-induced neuroinflammation, edema, and neurologic deficit. PubMed:24904418
Indeed, TLRs and NLRP3 have been associated with atherosclerosis development. PubMed:24904418
Haem also induces tumour necrosis factor (TNF) secretion in monocyte/macrophages through TLR4 and the adaptor molecule, MYD88 (Figueiredo et al, 2007). PubMed:25307023
Other studies demonstrated that heme can trigger the activation of Toll-like receptor 4 and inflammasomes, thus leading to inflammatory reactions.5,35–37 PubMed:26794659
Cell-free heme selectively triggers pro-inflammatory receptors such as TLR-4 and BACH-1, and activates proteasomes25. PubMed:27515135
The released heme can activate the innate immune pattern recognition receptor toll-like receptor 4 (TLR4) on inflammatory cells, platelets and endothelium, promoting a pro-inflammatory and pro-coagulant phenotype, ultimately leading to vaso-occlusion, ischemia-reperfusion physiology, tissue injury, and pain in murine models of SCD [5, 7±10]. PubMed:29694434
Other studies demonstrated that heme can trigger the activation of Toll-like receptor 4 and inflammasomes, thus leading to inflammatory reactions.5,35–37 PubMed:26794659
The released heme can activate the innate immune pattern recognition receptor toll-like receptor 4 (TLR4) on inflammatory cells, platelets and endothelium, promoting a pro-inflammatory and pro-coagulant phenotype, ultimately leading to vaso-occlusion, ischemia-reperfusion physiology, tissue injury, and pain in murine models of SCD [5, 7±10]. PubMed:29694434
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