Toll-like Receptor Signaling Cascade Research Articles

Current trends in the role of neuroinflammation & α-synuclein in alcohol use disorder: A systematic quantitative literature review.

The neurodegenerative effects alcohol use disorder (AUD) have been well characterized and are likely due to the long-term effects of alcohol on the brain. The molecular events that underlie regional neuronal loss are a focus of current research. Chronic inflammation in the central nervous system, termed neuroinflammation, contributes to the progressive loss of neurons in the brain. Using data from genome-wide association studies and genetic and gene expression data, α-synuclein was identified as a gene of interest for AUD almost 10 years ago. Despite this and the well-recognized role of α-synuclein in mediating neuroinflammation in other neurodegenerative diseases, its role in alcohol-induced brain damage and AUD is yet to be elucidated. This systematic literature review quantifies and analyzes relationships between AUD, α-synuclein, and neuroinflammation. The review identified fewer studies focused on the role in AUD of α-synuclein (30) than on neuroinflammation (177), with published studies heavily centered on the myeloid differentiation primary response 88 (MyD88)-dependent toll-like receptor 4 (TLR4) pathway. The systematic review revealed that no original literature investigates the roles of α-synuclein and neuroinflammation in AUD and that there are significantly fewer published articles on the role of α-synuclein in AUD than in other neuroinflammatory conditions. Studies of the role of neuroinflammation in AUD are largely centered on the TLR4 signaling cascade, followed by TLR2 and TLR3, and soluble cytokines such as IL-10, IL-1β, and TNF-α. Key research themes identified in other neurodegenerative disorders provide new insights for further investigation in AUD.

Respiratory Diseases Associated With Organic Dust Exposure

Organic dusts are complex bioaerosol mixtures comprised of dust and par ticulate matter of organic origin. These include components from bacteria, fungi, pollen, and viruses to fragments of animals and plants commonplace to several environmental/occupational settings encompassing agriculture/farming, grain processing, waste/recycling, textile, cotton, woodworking, bird breeding, and more. Organic dust exposures are linked to development of chronic bronchitis, chronic obstructive pulmonary disease, asthma, asthma-like syndrome, byssinosis, hypersensitivity pneumonitis, and idiopathic pulmonary fibrosis. Risk factors of disease development include cumulative dust exposure, smoking, atopy, timing/duration, and nutritional factors. The immunopathogenesis predominantly involves Toll-like receptor signaling cascade, T-helper 1/T-helper 17 lymphocyte responses, neutrophil influx, and potentiation of manifestations associated with allergy. The true prevalence of airway disease directly attributed to organic dust, especially in a workplace setting, remains challenging. Diagnostic confirmation can be difficult and complicated by hesitancy from workers to seek medical care, driven by fears of potential labor-related consequence. Clinical respiratory and systemic presentations coupled with allergy testing, lung function patterns of obstructive versus restrictive disease, and radiological characteristics are typically utilized to delineate these various organic dust-associated respiratory diseases. Prevention, risk reduction, and management primarily focus on reducing exposure to the offending dust, managing symptoms, and preventing disease progression.

Immunological characterization and diagnostic models of RNA N6-methyladenosine regulators in Alzheimer's disease

Alzheimer's disease (AD) is the most prevalent form of dementia, and it displays both clinical and molecular variability. RNA N6-methyladenosine (m6A) regulators are involved in a wide range of essential cellular processes. In this study, we aimed to identify molecular signatures associated with m6A in Alzheimer's disease and use those signatures to develop a predictive model. We examined the expression patterns of m6A regulators and immune features in Alzheimer’s disease using the GSE33000 dataset. We examined the immune cell infiltration and molecular groups based on m6A-related genes in 310 Alzheimer's disease samples. The WGCNA algorithm was utilized to determine differently expressed genes within each cluster. After evaluating the strengths and weaknesses of the random forest model, the support vector machine model, the generalized linear model, and eXtreme Gradient Boosting, the best machine model was selected. Methods such as nomograms, calibration curves, judgment curve analysis, and the use of independent data sets were used to verify the accuracy of the predictions made. Alzheimer's disease and non-disease Alzheimer's groups were compared to identify dysregulated m6A-related genes and activated immune responses. In Alzheimer's disease, two molecular clusters linked to m6A were identified. Immune infiltration analysis indicated substantial variation in protection between groups. Cluster 1 included processes like the Toll-like receptor signaling cascade, positive regulation of chromatin binding, and numerous malignancies; cluster 2 included processes like the cell cycle, mRNA transport, and ubiquitin-mediated proteolysis. With a lower residual and root mean square error and a larger area under the curve (AUC = 0.951), the Random forest machine model showed the greatest discriminative performance. The resulting random forest model was based on five genes, and it performed well (AUC = 0.894) on external validation datasets. Accuracy in predicting Alzheimer's disease subgroups was also shown by analyses of nomograms, calibration curves, and decision curves. In this research, we methodically outlined the tangled web of connections between m6A and AD and created a promising prediction model for gauging the correlation between m6A subtype risk and AD pathology.

Prenatal alcohol exposure alters mRNA expression for stress peptides, glucocorticoid receptor function and immune factors in acutely stressed neonatal brain.

The amygdala, hippocampus and hypothalamus are critical stress regulatory areas that undergo functional maturation for stress responding initially established during gestational and early postnatal brain development. Fetal alcohol spectrum disorder (FASD), a consequence of prenatal alcohol exposure (PAE), results in cognitive, mood and behavioral disorders. Prenatal alcohol exposure negatively impacts components of the brain stress response system, including stress-associated brain neuropeptides and glucocorticoid receptors in the amygdala, hippocampus and hypothalamus. While PAE generates a unique brain cytokine expression pattern, little is known about the role of Toll-like receptor 4 (TLR4) and related proinflammatory signaling factors, as well as anti-inflammatory cytokines in PAE brain stress-responsive regions. We hypothesized that PAE sensitizes the early brain stress response system resulting in dysregulated neuroendocrine and neuroimmune activation. A single, 4-h exposure of maternal separation stress in male and female postnatal day 10 (PND10) C57Bl/6 offspring was utilized. Offspring were from either prenatal control exposure (saccharin) or a limited access (4 h) drinking-in-the-dark model of PAE. Immediately after stress on PND10, the hippocampus, amygdala and hypothalamus were collected, and mRNA expression was analyzed for stress-associated factors (CRH and AVP), glucocorticoid receptor signaling regulators (GAS5, FKBP51 and FKBP52), astrocyte and microglial activation, and factors associated with TLR4 activation including proinflammatory interleukin-1β (IL-1β), along with additional pro- and anti-inflammatory cytokines. Select protein expression analysis of CRH, FKBP and factors associated with the TLR4 signaling cascade from male and female amygdala was conducted. The female amygdala revealed increased mRNA expression in stress-associated factors, glucocorticoid receptor signaling regulators and all of the factors critical in the TLR4 activation cascade, while the hypothalamus revealed blunted mRNA expression of all of these factors in PAE following stress. Conversely, far fewer mRNA changes were observed in males, notably in the hippocampus and hypothalamus, but not the amygdala. Statistically significant increases in CRH protein, and a strong trend in increased IL-1β were observed in male offspring with PAE independent of stressor exposure. Prenatal alcohol exposure creates stress-related factors and TLR-4 neuroimmune pathway sensitization observed predominantly in females, that is unmasked in early postnatal life by a stress challenge.

Potential role of EBV and Toll-like receptor 9 ligand in patients with systemic lupus erythematosus.

SLE is a multisystem autoimmune disease characterized by multiple immunological abnormalities including production of autoantibodies. While the etiology of SLE is largely unknown, it is generally accepted that both genetic and environmental factors contribute to disease risk and immune dysregulation. Production of IFN-α is important for protecting the host against infections; however, over stimulation of innate immune pathways can induce autoimmune disease. Environmental factors, particularly Epstein-Barr virus (EBV), have been proposed to play an important role in SLE disease. Improper engagement of Toll-like receptor (TLR) pathways by endogenous or exogenous ligands may lead to the initiation of autoimmune responses and tissue injury. EBV is shown to be a potent stimulant of IFN-α by TLR signaling cascades. Given the highlighted role of IFN-α in SLE pathogenesis and potential role of EBV infection in this disease, the present study is aimed at exploring the in vitro effects of EBV infection and CPG (either alone or in combination) on IFN-α. We also examined the expression level of CD20 and BDCA-4 and CD123 in PBMCs in 32 SLE patients and 32 healthy controls. Our results showed PBMCs treated with CPG-induced higher levels of IFN-α and TLR-9 gene expression fold change compared to cells treated with either EBV or EBV-CPG. Moreover, PBMCs treated with CPG produced significantly higher IFN-α concentration in supernatant compared to cells treated with EBV but not EBV-CPG. Our results further highlight the potential role of EBV infection and TLRs in SLE patients although more studies are warranted to ascertain the global imprint that EBV infection can have on immune signature in patients with SLE.

Dihydromyricetin alleviates methotrexate-induced hepatotoxicity via suppressing the ‎TLR4/NF-κB pathway and NLRP3 inflammasome/caspase 1 axis

The anticancer drug methotrexate (MTX) is known to cause hepatotoxicity as a possibly fatal adverse effect that hinders its clinical application. Although the natural flavonoid, dihydromyricetin (DHM), has antioxidant and anti-inflammatory effects; its role against MTX-induced hepatotoxicity has not been explored yet. For this, rats were administrated DHM orally for two weeks at a dose of 300 mg/kg per day, with or without a single i.p. injection of 40 mg/kg MTX on the 9th day of the experiment. MTX caused deterioration in liver structure and function, depicted by an increase in liver enzymes; ALT and AST. Moreover, MTX induced oxidative stress, shown by increasing malondialdehyde and decreasing reduced glutathione and total antioxidant capacity, initiated the inflammatory response via upregulated expression of Toll-like receptor 4 (TLR4) and its downstream transcription factor, nuclear factor-kappa B (NF-κB p65). Consequent to TLR4 signaling cascade, Nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammosome was activated and caused caspase 1 mediated transformation of proinflammatory cytokines interleukin 1β (IL-1β) and interleukin 18 (IL-18) into their active forms. Interestingly, administering DHM with MTX improved liver structure and function, as well as significantly decreased all oxidative stress and inflammatory signaling. Collectively, DHM possesses antioxidant and anti-inflammatory properties that can ameliorate MTX-induced hepatotoxicity, through down-regulation of liver TLR4/NF-κB and therefore prohibit activation of NLRP3/caspase 1 pathway.

Oleuropein ameliorated lung ischemia-reperfusion injury by inhibiting TLR4 signaling cascade in alveolar macrophages

Lung ischemia–reperfusion (I/R) injury is a common postoperative complication in patients with lung transplantation, pulmonary embolism, and cardiopulmonary bypass. Lung I/R injury is a sterile inflammatory process that leads to lung dysfunction, and is an important cause of patient death. Effectively alleviating lung I/R injury can thus improve the prognosis of patients. In this study, we created a mouse model of lung I/R injury by transient unilateral left pulmonary artery occlusion. 6–8 weeks male C57BL/6 mice were randomly assigned to four groups: Sham, I/R, I/R + oleuropein (OLE) and OLE. OLE (50 mg/kg) was orally 24 h and 30 min before anesthesia. Measurement of lung pathohistological, isolated alveolar macrophages (AMs), inflammatory mediators, TLR4 and its downstream factors (MyD88, NF-κB) were performed. We then evaluated the ability of oleuropein (OLE) to ameliorate I/R-induced lung injury and explored the possible molecular mechanisms. OLE ameliorated I/R-induced lung injury and edema and decreased inflammatory factors in lung tissue and bronchoalveolar lavage fluid. This protection required toll-like receptor 4 (TLR4). OLE significantly inhibited I/R-induced expression of TLR4 and its downstream factors in lung tissue and alveolar macrophages. In addition, hypoxia-inducible factor 1α protein accumulated in TLR4-mediated lung I/R injury, and further induced the production of inflammatory factors. Collectively, these data suggest that OLE ameliorates I/R-induced lung injury. The mechanism responsible for its protective effect may involve inhibition of the I/R-induced inflammatory response by downregulating the TLR4 signaling cascade in AMs.

Regulatory strategies limiting endosomal Toll-like receptor activation in B cells.

The recognition of pathogen-associated nucleic acid (NA) promotes effective immunity against invading pathogens. However, endosomal Toll-like receptor (TLR) activation by self-NA also underlies the pathogenesis of systemic autoimmune diseases, such as systemic lupus erythematosus (SLE). For this reason, the activation thresholds of NA-sensing TLRs must be tightly regulated to balance protective and pathogenic immune responses. In this study, we will provide an overview of the evolutionary mechanisms designed to limit the aberrant activation of endosomal TLRs by self-ligands, focusing on four broad strategies. These include the following: 1) the production of nucleases able to degrade self-DNA and RNA; 2) the cell-specific regulation of endosomal TLR expression; 3) the spatial and temporal control of TLR positioning at a sub-cellular level; and 4) the modulation of downstream TLR signaling cascades. Given the critical role of B cells in lupus pathogenesis, where possible, we will describe evidence for B cell-specific induction of these regulatory mechanisms. We will also highlight our own work showing how modulation of B cell endolysosomal flux tunes NA-sensing TLR activation signals. In the face of inevitable generation of self-NA during normal cellular turnover, these parallel mechanisms are vital to protect against pathogenic inflammation.

Interaction between polysaccharides and toll-like receptor 4: Primary structural role, immune balance perspective, and 3D interaction model hypothesis

Various structural types of polysaccharides are recognized by toll-like receptor 4 (TLR4). However, the mechanism of interaction between the polysaccharides with different structures and TLR4 is unclarified. This review summarized the primary structure of polysaccharides related to TLR4, mainly including molecular weight, monosaccharide composition, glycosidic bonds, functional groups, and branched-chain structure. The optimal primary structure for interacting with TLR4 was obtained by the statistical analysis. Besides, the dual-directional regulation of TLR4 signaling cascade by polysaccharides was also elucidated from an immune balance perspective. Finally, the 3D interaction model of polysaccharides to TLR4-myeloid differentiation factor 2 (MD2) complex was hypothesized according to the LPS-TLR4-MD2 dimerization model and the polysaccharides solution conformation. The essence of polysaccharides binding to TLR4-MD2 complex is a multivalent non-covalent bond interaction. All the arguments summarized in this review are intended to provide some new insights into the interaction between polysaccharides and TLR4.

Protective role of TIRAP functional variant against development of coronary artery disease.

Coronary artery disease (CAD) is the leading cause of sudden death worldwide. Inflammation is proved to be an important player in development of the CAD. Inflammation is directly regulated by the Toll like receptors (TLRs). Susceptibility of CAD is influenced by genetic variations within TLRs and the proteins involved in its signaling cascade. The TIRAP/MAL {TIR domain containing adaptor protein / MyD88 (myeloid differentiation primary response gene 88) adaptor-like} exhibits maximum genetic variations of all adaptor proteins involved in TLR signaling cascade. Susceptibility to a number of diseases can be influenced due to presence of S180L single nucleotide polymorphism (SNP) of TIRAP/MAL. This study was conducted to investigate the functional role of this well characterized S180L polymorphism on susceptibility to CAD among Pakistani patients. A total of 146 Pakistani CAD patients and 147 controls were genotyped by Amplification Refractory Mutation System-Polymerase Chain Reaction (ARMS-PCR) and the data was analyzed by using 2-tailed Chi square (x2) test. The p value ≤ 0.05 was considered to be significant.Significantly high frequency of homozygous L180L genotype was observed among healthy subjects as compared to the CAD patients [24 (16%) vs 7 (5%); x2 11.85; p = 0.003]. Moreover, the allele frequency of the minor allele; 180L was observed to be significantly higher among controls than the CAD patients, having same direction of association [156 (53%) vs 131 (45%); OR (95% CI) = 0.7198 (0.520–0.996); p < 0.05).Our results indicate that protective effect of L180L; a coding variant of TIRAP/MAL against CAD is discernible.

Deletion of TLR4 attenuates lipopolysaccharide-induced acute liver injury by inhibiting inflammation and apoptosis.

Septic acute liver injury is one of the leading causes of fatalities in patients with sepsis. Toll-like receptor 4 (TLR4) plays a vital role in response to lipopolysaccharide (LPS) challenge, but the mechanisms underlying TLR4 function in septic injury remains unclear. In this study, we investigated the role of TLR4 in LPS-induced acute liver injury (ALI) in mice with a focus on inflammation and apoptosis. Wild-type (WT) and TLR4-knockout (TLR4-/-) mice were challenged with LPS (4 mg/kg) for 6 h. TLR4 signaling cascade markers (TLR4, MyD88, and NF-κB), inflammatory markers (TNFα, IL-1β, and IL-6), and apoptotic markers (Bax, Bcl-2, and caspase 3) were evaluated. We showed that LPS challenge markedly increased the levels of serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) and other liver pathological changes in WT mice. In addition, LPS challenge elevated the levels of liver carbonyl proteins and serum inflammatory cytokines, upregulated the expression of TLR4, MyD88, and phosphorylated NF-κB in liver tissues. Moreover, LPS challenge significantly increased hepatocyte apoptosis, caspase 3 activity, and Bax level while suppressing Bcl-2 expression in liver tissues. These pathological changes were greatly attenuated in TLR4-/- mice. Similar pathological responses were provoked in primary hepatic Kupffer cells isolated from WT and TLR4-/- mice following LPS (1 μg/mL, 6 h) challenge. In summary, these results demonstrate that silencing of TLR4 attenuates LPS-induced liver injury through inhibition of inflammation and apoptosis via TLR4/MyD88/NF-κB signaling pathway. TLR4 deletion confers hepatoprotection against ALI induced by LPS, possibly by repressing macrophage inflammation and apoptosis.

Molecular alterations of the TLR4-signaling cascade in canine epilepsy

BackgroundCumulating evidence from rodent models points to a pathophysiological role of inflammatory signaling in the epileptic brain with Toll-like receptor-4 signaling acting as one key factor. However, there is an apparent lack of information about expression alterations affecting this pathway in canine patients with epilepsy. Therefore, we have analyzed the expression pattern of Toll-like receptor 4 and its ligands in brain tissue of canine patients with structural or idiopathic epilepsy in comparison with tissue from laboratory dogs or from owner-kept dogs without neurological diseases.ResultsThe analysis revealed an overexpression of Toll-like receptor-4 in the CA3 region of dogs with structural epilepsy. Further analysis provided evidence for an upregulation of Toll-like receptor-4 ligands with high mobility group box-1 exhibiting increased expression levels in the CA1 region of dogs with idiopathic and structural epilepsy, and heat shock protein 70 exhibiting increased expression levels in the piriform lobe of dogs with idiopathic epilepsy. In further brain regions, receptor and ligand expression rates proved to be either in the control range or reduced below control levels.ConclusionsOur study reveals complex molecular alterations affecting the Toll-like receptor signaling cascade, which differ between epilepsy types and between brain regions. Taken together, the data indicate that multi-targeting approaches modulating Toll-like receptor-4 signaling might be of interest for management of canine epilepsy. Further studies are recommended to explore respective molecular alterations in more detail in dogs with different etiologies and to confirm the role of the pro-inflammatory signaling cascade as a putative target.

Baicalin and its nanoliposomes ameliorates nonalcoholic fatty liver disease via suppression of TLR4 signaling cascade in mice

As a natural flavonoid compound, baicalin(BA)has been reported to exhibit hepatoprotective and anti-inflammatory properties. However, the characteristic of poor solubility and low bioavailability greatly limits its application. In addition, the effects and underlying mechanisms of BA in nonalcoholic fatty liver disease (NAFLD) remain elusive. In this study, Methionine and choline deficient diet (MCD)-induced NAFLD mice were treated with baicalin or baicalin-loaded nanoliposomes (BA-NL), then hepatic histopathological changes, biochemical parameters and inflammatory molecules were observed. We found that mice in MCD group showed significant increases in plasma transaminase, hepatocyte apoptosis, hepatic lipid accumulation, liver fibrosis, and infiltration of neutrophils and macrophages compared with control group, however, BA and BA-NL markedly attenuated MCD-induced the above changes. Besides, further analysis indicated that BA and BA-NL also inhibited the up-regulation of toll-like receptor 4 (TLR4) signal and the production of inflammatory mediators in MCD mice. Importantly, BA-NL was found to be more effective than baicalin on MCD-induced NAFLD in mice. These data suggested that BA and its nanoliposomes BA-NL could effectively protect mice against MCD-induced NAFLD, which might be mediated through inhibiting TLR4 signaling cascade.

Sitagliptin ameliorates thioacetamide-induced acute liver injury via modulating TLR4/NF-KB signaling pathway in mice

Sitagliptin is an oral hypoglycemic drug that acts by selective inhibition of dipeptidyl peptidase-4 (DDP-4) enzyme. AimThis study scrutinized the hepatoprotective impact of sitagliptin) against thioacetamide (TAA)-induced liver damage in mice. Main methodsMale mice were injected with TAA (500 mg/kg) then treated with sitagliptin (20 mg/kg) orally for 5 days. Key findingsHistopathological results of TAA group revealed severe degree of centrolobular hepatic necrosis. Additionally, biochemical findings showed marked elevation in the serum transaminases and gamma glutamyl transpeptidase (GGT) levels in TAA group. Injection of TAA significantly disrupted oxidant/antioxidants hemostasis of the hepatic tissues. Also, TAA markedly increased the expression of nuclear factor kappa-B (NF-KB); and enhanced Toll like receptor 4 (TLR4) as well as NLPR3 inflammosome production. Moreover, there was an elevation in the hepatic levels of tumor necrosis factor-alpha (TNF-α) and interleukin -1 beta (IL-1β) besides increased immunoexpression of Bcl-2-associated X protein (Bax) as well as caspase 3. In contrast, treatment with sitagliptin significantly attenuated TAA-induced histopathological, biochemical and immunohistochemical alterations. SignificanceOur results suggest that the hepatoprophylactic impact of sitagliptin might be arbitrated via modulating TLR4 and NK-KB signaling cascade followed by depression of inflammation besides apoptosis.

Current and Emerging Evidence for Toll-Like Receptor Activation in Sjögren's Syndrome.

While the importance of Toll-like receptor (TLR) signaling is well established in many autoimmune diseases, the role of TLR activation in Sjögren's syndrome (SS) is poorly understood. Studies in mice and humans reveal that TLRs are potent mediators of inflammation in SS. TLRs are expressed and functional in salivary tissue, and TLRs in peripheral blood cells of SS patients are also upregulated and hyperresponsive to ligation. In this review, we will detail observations in mouse models regarding the importance of TLR activation in both local and systemic disease. We will then discuss studies in SS patients that provide evidence of the importance of TLR-mediated signaling in disease. While the ligands that activate TLRs in the context of SS are unknown, emerging data suggest that damage-associated molecular patterns (DAMPs) may be significant drivers of the chronic and unremitting inflammation that is characteristic of SS. We will discuss putative DAMPs that may be of clinical significance in disease. Therapies that target TLR signaling cascades will likely reduce both exocrine-specific and systemic manifestations of SS.

Preclinical Activity of IRAK4 Kinase Inhibitor CA-4948 Alone or in Combination with Targeted Therapies and Preliminary Phase 1 Clinical Results in Non-Hodgkin Lymphoma

Preclinical Activity of IRAK4 Kinase Inhibitor CA-4948 Alone or in Combination with Targeted Therapies and Preliminary Phase 1 Clinical Results in Non-Hodgkin Lymphoma

Effect of celastrol on toll‑like receptor 4‑mediated inflammatory response in free fatty acid‑induced HepG2 cells.

Toll-like receptor 4 (TLR4)-mediated immune and inflammatory signaling serves a pivotal role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Our previous study demonstrated that celastrol treatment was able to improve hepatic steatosis and inhibit the TLR4 signaling cascade pathway in type 2 diabetic rats. The present study aimed to investigate the effects of celastrol on triglyceride accumulation and inflammation in steatotic HepG2 cells, and the possible mechanisms responsible for the regulation of cellular responses following TLR4 gene knockdown by small interfering RNA (siRNA) in vitro. A cell model of hepatic steatosis was prepared by exposing the HepG2 cells to free fatty acid (FFA) in the absence or presence of celastrol. Intracellular triglycerides were visualized by Oil red O staining, and the TLR4/myeloid differentiation primary response 88 (MyD88)/nuclear factor-κB (NF-κB) signaling cascade pathway were investigated. To directly elucidate whether TLR4 was the blocking target of celastrol upon FFA exposure, the cellular response to inflammation was determined upon transfection with TLR4 siRNA. The results revealed that celastrol significantly reduced triglyceride accumulation in the steatotic HepG2 cells, and downregulated the expression levels of TLR4, MyD88 and phospho-NF-κBp65, as well as of the downstream inflammatory cytokines interleukin-1β and tumor necrosis factor α. Knockdown of TLR4 also alleviated FFA-induced inflammatory response. In addition, co-treatment with TLR4 siRNA and celastrol further attenuated the expression of inflammatory mediators. These results suggest that celastrol exerts its protective effect partly via inhibiting the TLR4-mediated immune and inflammatory response in steatotic HepG2 cells.

Decoy peptide targeted to Toll-IL-1R domain inhibits LPS and TLR4-active metabolite morphine-3 glucuronide sensitization of sensory neurons

Accumulating evidence indicates that Toll-like receptor (TLR) signaling adapter protein interactions with Toll/Interleukin-1 Receptor (TIR) domains present in sensory neurons may modulate neuropathic pain states. Following ligand interaction with TLRs, TIR serves to both initiate intracellular signaling and facilitate recruitment of signaling adapter proteins to the intracytoplasmic domain. Although TLR TIR is central to a number of TLR signaling cascades, its role in sensory neurons is poorly understood. In this study we investigated the degree to which TLR TIR decoy peptide modified to include a TAT sequence (Trans-Activator of Transcription gene in HIV; TAT-4BB) affected LPS-induced intracellular calcium flux and excitation in sensory neurons, and behavioral changes due to TLR4 active metabolite, morphine-3-glucuronide (M3G) exposure in vivo. TAT-4BB inhibited LPS-induced calcium changes in a majority of sensory neurons and decreased LPS-dependent neuronal excitability in small diameter neurons. Acute systemic administration of the TAT-4BB reversed M3G-induced tactile allodynia in a dose-dependent manner but did not affect motor activity, anxiety or responses to noxious thermal stimulus. These data suggest that targeting TLR TIR domains may provide novel pharmacological targets to reduce or reverse TLR4-dependent pain behavior in the rodent.

Wnt/TLR Dialog in Neuroinflammation, Relevance in Alzheimer's Disease.

The innate immune system (IIS) represents the first line of defense against exogenous and endogenous harmful stimuli. Different types of pathogens and diverse molecules can activate the IIS via a ligand–receptor mechanism. Cytokine release, recruitment of immunocompetent cells, and inflammation constitute the initial steps in an IIS-mediated response. While balanced IIS activity can resolve a harmful event, an altered response, such as deficient or persistent IIS activity, will have a critical effect on organism homeostasis. In this regard, chronic IIS activation has been associated with a wide range of diseases, including chronic inflammatory disorders (inflammatory bowel disease, arthritis, chronic obstructive pulmonary disease, among others), cancer and, more recently, neurodegenerative disorders. The relevance of the immune response, particularly inflammation, in the context of neurodegeneration has motivated rigorous research focused on unveiling the mechanisms underlying this response. Knowledge regarding the molecular hallmarks of the innate immune response and understanding signaling pathway cross talk are critical for developing new therapeutic strategies aimed at modulating the neuroinflammatory response within the brain. In the present review, we discuss the IIS in the central nervous system, particularly the cross talk between the toll-like receptor-signaling cascade and the wingless-related MMTV integration site (Wnt) signaling pathway and its relevance in neurodegenerative disorders such as Alzheimer’s disease.

MiR-146a/b: a family with shared seeds and different roots.

MicroRNAs are small, noncoding, RNAs known for their powerful modulation of molecular processes, making them a major focus for studying pathological mechanisms. The human miR-146 family of microRNAs consists of two member genes, MIR146A and MIR146B These two microRNAs are located on different chromosomes and exhibit differential regulation in many cases. However, they are nearly identical in sequence, sharing a seed region, and are thus predicted to target the same set of genes. A large proportion of the microRNA (miR)-146 literature focuses on its role in regulating the innate immune response in the context of various pathologies by modulating two widely studied target genes in the toll-like receptor signaling cascade. A growing subset of the literature reports a role of miR-146 in cardiovascular and renal disease, and data suggest there is exciting potential for miR-146 as a diagnostic and therapeutic target. Nevertheless, the published literature is confounded by unclear and imprecise language concerning the specific effects of the two miR-146 family members. The present review will compare the genomic origin and regulation of miR-146a and miR-146b, discuss some approaches to overcome analytical and experimental challenges, and summarize findings in major areas of miR-146 research. Moving forward, careful evaluation of miR-146a/b specificity in analytical and experimental approaches will aid researchers in elucidating the functional relevance of differential regulation of the miR-146 family members in health and disease.