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Subarachnoid hemorrhage (SAH) is a life-threatening cerebrovascular disease with high rates of morbidity and mortality and a paucity of effective therapies. The development of early brain injury (EBI) is closely related to prognosis in SAH, and inflammation plays an important role in its pathophysiology. A previous experiment showed that ST2825, a selective inhibitor of MyD88, could alleviate EBI in vivo. However, this protective effect in vivo is affected by a variety of pathophysiology processes making the result to some extent uncertain. whether there is a coincident result in vitro ruling out the effect of other factors remains unknown, and further investigation using cultured neurons is necessary. Primary neuronal cells were cultured to construct an in vitro model of SAH. The cells were cultured and then divided into three groups: (1) a blank control group, (2) an oxygenated hemoglobin + vehicle group, and (3) an oxygenated hemoglobin + ST2825 group. In each group, apoptosis of neuronal cells along with changes in the expression of proteins including MyD88, p-JNK, p-Erk, p-p38, NFκB, Bcl-2, and P53 were measured. Results showed that after stimulating neurons with oxygenated hemoglobin, the expression of the MyD88 protein in the vehicle group increased significantly. The quantity of p-JNK, p-p38, and p-Erk also increased significantly, as did the quantity of p65 in the nucleus. Expression of the antiapoptotic protein Bcl-2 was markedly reduced, while that of the cleaved caspase-3 protein was significantly increased. In addition, in this group, the apoptosis rate of neurons was significantly increased. In the ST2825 group, the expression of p-JNK, p-p38, p-Erk, cleaved caspase-3, and p65 in the nucleus was significantly decreased, the expression of Bcl-2 was significantly increased, and the apoptosis rate of neurons was significantly reduced. The results of this study suggest that in an experimental in vitro SAH model, ST2825, a selective inhibitor of MyD88, can have a neuroprotective effect by inhibiting neuronal apoptosis mediated by the MAPK and NFκB signaling pathways, and this has a certain protective effect on EBI after SAH. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a neuro-autoimmune and neurodegenerative disorder leading to chronic inflammation, demyelination, axonal, and neuronal loss in the central nervous system (CNS). Despite intense research efforts, the pathogenesis of MS still remains unclear. Toll-like receptors (TLRs) are a family of type I transmembrane receptors that play a crucial role in the innate immune response. Myeloid differentiation factor 88 (MyD88) is the adaptor of major TLRs. It has been widely considered that the TLR-MyD88 signaling pathway plays an important role in the occurrence and development of autoimmune disease. Data have revealed that the TLR-MyD88 signaling may be involved in the pathogenesis of MS and experimental autoimmune encephalomyelitis (EAE), an animal model for MS, by regulating the antigen presentation of dendritic cells, the integrity of blood-brain barrier (BBB), and the activation of T cells and B cells. Here, we summarize the role of TLRs and MyD88 in MS and discuss the possible therapies that are based on these molecules.

Multiple sclerosis (MS) is a neuro-autoimmune and neurodegenerative disorder leading to chronic inflammation, demyelination, axonal, and neuronal loss in the central nervous system (CNS). Despite intense research efforts, the pathogenesis of MS still remains unclear. Toll-like receptors (TLRs) are a family of type I transmembrane receptors that play a crucial role in the innate immune response. Myeloid differentiation factor 88 (MyD88) is the adaptor of major TLRs. It has been widely considered that the TLR-MyD88 signaling pathway plays an important role in the occurrence and development of autoimmune disease. Data have revealed that the TLR-MyD88 signaling may be involved in the pathogenesis of MS and experimental autoimmune encephalomyelitis (EAE), an animal model for MS, by regulating the antigen presentation of dendritic cells, the integrity of blood-brain barrier (BBB), and the activation of T cells and B cells. Here, we summarize the role of TLRs and MyD88 in MS and discuss the possible therapies that are based on these molecules. [ABSTRACT FROM AUTHOR]

The innate immune system is the first line of defense against pathogens, which is initiated by the recognition of pathogen-associated molecular patterns (PAMPs) and endogenous damage-associated molecular patterns (DAMPs) by pattern recognition receptors (PRRs). Among all the PRRs identified, the toll-like receptors (TLRs) are the most ancient class, with the most extensive spectrum of pathogen recognition. Since the first discovery of Toll in Drosophila melanogaster, numerous TLRs have been identified across a wide range of invertebrate and vertebrate species. It seems that TLRs, the signaling pathways that they initiate, or related adaptor proteins are essentially conserved in a wide variety of organisms, from Porifera to mammals. Molecular structure analysis indicates that most TLR homologs share similar domain patterns and that some vital participants of TLR signaling co-evolved with TLRs themselves. However, functional specification and emergence of new signaling pathways, as well as adaptors, did occur during evolution. In addition, ambiguities and gaps in knowledge still exist regarding the TLR network, especially in lower organisms. Hence, a systematic review from the comparative angle regarding this tremendous signaling system and the scenario of evolutionary pattern across Animalia is needed. In the current review, we present overview and possible evolutionary patterns of TLRs in non-mammals, hoping that this will provide clues for further investigations in this field.

The innate immune system is the first line of defense against pathogens, which is initiated by the recognition of pathogen-associated molecular patterns (PAMPs) and endogenous damage-associated molecular patterns (DAMPs) by pattern recognition receptors (PRRs). Among all the PRRs identified, the toll-like receptors (TLRs) are the most ancient class, with the most extensive spectrum of pathogen recognition. Since the first discovery of Toll in Drosophila melanogaster, numerous TLRs have been identified across a wide range of invertebrate and vertebrate species. It seems that TLRs, the signaling pathways that they initiate, or related adaptor proteins are essentially conserved in a wide variety of organisms, from Porifera to mammals. Molecular structure analysis indicates that most TLR homologs share similar domain patterns and that some vital participants of TLR signaling co-evolved with TLRs themselves. However, functional specification and emergence of new signaling pathways, as well as adaptors, did occur during evolution. In addition, ambiguities and gaps in knowledge still exist regarding the TLR network, especially in lower organisms. Hence, a systematic review from the comparative angle regarding this tremendous signaling system and the scenario of evolutionary pattern across Animalia is needed. In the current review, we present overview and possible evolutionary patterns of TLRs in non-mammals, hoping that this will provide clues for further investigations in this field. [ABSTRACT FROM AUTHOR]

Background. Q fever is an infection caused by Coxiella burnetii. Persistent infection (chronic Q fever) develops in 1%-5% of patients. We hypothesize that inefficient recognition of C. burnetii and/or activation of host-defense in individuals carrying genetic variants in pattern recognition receptors or adaptors would result in an increased likelihood to develop chronic Q fever. Methods. Twenty-four single-nucleotide polymorphisms in genes encoding Toll-like receptors, nucleotide-binding oligomerization domain-like receptor-2, αvβ3 integrin, CR3, and adaptors myeloid differentiation primary response protein 88 (MyD88), and Toll interleukin 1 receptor domain-containing adaptor protein (TIRAP) were genotyped in 139 patients with chronic Q fever and in 220 controls with cardiovascular risk-factors and previous exposure to C. burnetii. Associations between these single-nucleotide polymorphisms and chronic Q fever were assessed by means of univariate logistic regression models. Cytokine production in whole-blood stimulation assays was correlated with relevant genotypes. Results. Polymorphisms in TLR1 (R80T), NOD2 (1007fsX1), and MYD88 (−938C>A) were associated with chronic Q fever. No association was observed for polymorphisms in TLR2, TLR4, TLR6, TLR8, ITGAV, ITGB3, ITGAM, and TIRAP. No correction for multiple testing was performed because only genes with a known role in initial recognition of C. burnetii were included. In the whole-blood assays, individuals carrying the TLR1 80R-allele showed increased interleukin 10 production with C. burnetii exposure. Conclusions. Polymorphisms in TLR1 (R80T), NOD2 (L1007fsX1), and MYD88 (−938C>A) are associated with predisposition to development of chronic Q fever. For TLR1, increased interleukin 10 responses to C. burnetii in individuals carrying the risk allele may contribute to the increased risk of chronic Q fever. [ABSTRACT FROM AUTHOR]

Abstract: Subarachnoid hemorrhage (SAH) which is mostly caused by aneurysm rupture causes a lot of death every year. Convincing evidence can be made that inflammation contributes to the poor outcome caused by SAH. Toll like receptors (TLRs), nuclear factor-kappaB (NF-κB), Interleukin 1β (IL-1β) and tumor necrosis factor-α (TNF-α) are involved in the damaging inflammation process after SAH. Myeloid differentiation primary response protein 88 (MyD88) is essential to deliver TLRs signals down to NF-κB and pro-inflammatory factors. The study aims to detect the expression level of MyD88 and know more about the role of MyD88 after SAH. Sprague Dawley (SD) rats were randomly divided into sham group and SAH groups at 2h, 6h, 12h and on day 1, day 2, day 3, day 5 and day 7. SAH groups suffered experimental subarachnoid hemorrhage by injection of 0.3ml autoblood into the prechiasmatic cistern. MyD88 expression is measured by western blot analysis, real-time polymerase chain reaction (PCR), immunohistochemistry and immunofluorescence. The levels of TNF-α and IL-1β were measured by real-time PCR. Our results demonstrated MyD88 expression was increased after SAH, and peaked on day 1 and day 5, which showed a parallel time course to the up-regulation of IL-1β, there was a highly positive relationship between them. Immunohistochemistry and immunofluorescence results indicated up-regulated MyD88 was mainly located in neurons while over expressed MyD88 could also be found in astrocytes and microglia. These results might have important implications during the administration of specific MyD88 antagonists in order to prevent or reduce inflammatory response following SAH. [Copyright &y& Elsevier]

Abstract: A growing body of evidence indicates that Toll-like receptors (TLRs) and Interleukin-1 (IL-1) family have been shown to be involved in the damaging inflammatory processes associated with stroke, infection, neoplasia, and other diseases in the central nervous system. Myeloid differentiation primary response protein 88 (Myd88) is a critical adaptor protein that transmits signals for TLRs and IL-1 family. Therefore, this study aimed to detect the expression of Myd88 protein and mRNA in a rat weight-dropping trauma model and to clarify the role of Myd88 after traumatic brain injury (TBI). A total of fifty-four Sprague Dawley (SD) rats were randomly divided into control group and TBI groups at hours 6, 12 and on day 1, day 2, day 3, and day 7. The TBI groups suffered experimental TBI by improved Feeney model. Myd88 expression is measured by Reverse Transcription PCR (RT-PCR), Western blot analysis and immunohistochemistry; and nuclear factor-kappaB (NF-κB) binding activity by electrophoretic mobility shift assay (EMSA); The levels of tumor necrosis factor-α (TNF-α) and Interleukin 1β (IL-1β) were measured by enzyme linked immunosorbent assay (ELISA) and the intercellular adhesion molecule-1 (ICAM-1) expression by immunohistochemistry. The expression of Myd88 in the injured brain was dramatically increased through 6h and 7days postinjury, and peaked on 3days. NF-κB, TNF-α, IL-1β and ICAM-1 also ascended significantly after TBI. Our data demonstrated that Myd88 was increasingly expressed in a parallel time course to the up-regulation of NF-κB, proinflammatory cytokines and ICAM-1 and there was a highly positive relationship among them. These findings might have important implications during the administration of specific Myd88 antagonists in order to prevent or reduce inflammatory response after TBI. [Copyright &y& Elsevier]

Chronic hepatitis B can lead to liver cirrhosis and primary hepatocellular carcinoma. The present study aimed to investigate whether C-X-C motif chemokine receptor 3 (CXCR3) regulates the genes in Toll-like receptors (TLRs)/myeloid differentiation primary response protein 88 (MyD88) signaling pathway in the development of hepatitis B into cirrhosis and liver cancer in vitro. A hepatitis B virus (HBV) overexpression lentivirus was constructed and infected into a LX-2 cell line to obtain stable HBV-overexpressing cells (named HBV-LX-2 cells). The CXCR3 gene was knocked down using small interfering RNA in HBV-LX-2 cells. Cell Counting Kit-8 assays, cell scratch tests and flow cytometry were used to detect cell proliferation, migration and apoptosis, respectively. The levels of IL-1β and IL-6 in serum samples of patients with liver cancer were measured via ELISA, and the collagen content in liver cancer tissues was detected using Masson staining. Western blotting was used to detect the expression levels of proteins in the TLRs/MyD88 signaling pathway. Excessive fibrosis was identified in the liver cancer tissues, and the serum levels of IL-6 and IL-1β were abnormally increased in patients with liver cancer. It was found that interfering with CXCR3 inhibited cell proliferation and migration, as well as promoted the apoptosis of HBV-LX-2 cells. Moreover, interfering with CXCR3 inhibited the expression levels of collagen type I α 1 chain and the proteins in the TLRs/MyD88 pathway. In conclusion, CXCR3 knockdown could inhibit the expression levels of proteins in the TLR4/MyD88 signaling pathway, decrease cell proliferation and migration, and promote cell apoptosis, thus inhibiting the development of liver cirrhosis to liver cancer. [ABSTRACT FROM AUTHOR]