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Previous studies reported the expression of toll-like receptors (TLRs), merely TLR2 and TLR4, and complement fragments (C3a, C5b9) in vitreoretinal disorders. Other than pathogens, TLRs can recognize endogenous products of tissue remodeling as damage-associated molecular pattern (DAMPs). The aim of this study was to confirm the expression of TLR2 and TLR4 in the fibrocellular membranes and vitreal fluids (soluble TLRs) of patients suffering of epiretinal membranes (ERMs) and assess their association with disease severity, complement fragments and inflammatory profiles. Twenty (n = 20) ERMs and twelve (n = 12) vitreous samples were collected at the time of the vitrectomy. Different severity-staged ERMs were processed for: immunolocalization (IF), transcriptomic (RT-PCR) and proteomics (ELISA, IP/WB, Protein Chip Array) analysis. The investigation of targets included TLR2, TLR4, C3a, C5b9, a few selected inflammatory biomarkers (Eotaxin-2, Rantes, Vascular Endothelial Growth Factor (VEGFA), Vascular Endothelial Growth Factor receptor (VEGFR2), Interferon-γ (IFNγ), Interleukin (IL1β, IL12p40/p70)) and a restricted panel of matrix enzymes (Matrix metalloproteinases (MMPs)/Tissue Inhibitor of Metallo-Proteinases (TIMPs)). A reduced cellularity was observed as function of ERM severity. TLR2, TLR4 and myD88 transcripts/proteins were detected in membranes and decreased upon disease severity. The levels of soluble TLR2 and TLR4, as well as C3a, C5b9, Eotaxin-2, Rantes, VEGFA, VEGFR2, IFNγ, IL1β, IL12p40/p70, MMP7 and TIMP2 levels were changed in vitreal samples. Significant correlations were observed between TLRs and complement fragments and between TLRs and some inflammatory mediators. Our findings pointed at TLR2 and TLR4 over-expression at early stages of ERM formation, suggesting the participation of the local immune response in the severity of disease. These activations at the early-stage of ERM formation suggest a potential persistence of innate immune response in the early phases of fibrocellular membrane formation. [ABSTRACT FROM AUTHOR]

Toll-like receptors (TLRs) induce innate immune responses through activation of intracellular signaling pathways, such as MAP kinase and NF-κB signaling pathways, and play an important role in host defense against bacterial or viral infections. Meanwhile, excessive activation of TLR signaling leads to a variety of inflammatory disorders, including autoimmune diseases. TLR signaling is therefore strictly controlled to balance optimal immune response and inflammation. However, its balancing mechanisms are not fully understood. In this study, we identified the E3 ubiquitin ligase LINCR/ NEURL3 as a critical regulator of TLR signaling. In LINCR-deficient cells, the sustained activation of JNK and p38 MAPKs induced by the agonists for TLR3, TLR4, and TLR5, was clearly attenuated. Consistent with these observations, TLR-induced production of a series of inflammatory cytokines was significantly attenuated, suggesting that LINCR positively regulates innate immune responses by promoting the activation of JNK and p38. Interestingly, our further mechanistic study identified MAPK phosphatase-1 (MKP1), a negative regulator of MAP kinases, as a ubiquitination target of LINCR. Thus, our results demonstrate that TLRs fine-tune the activation of MAP kinase pathways by balancing LINCR (the positive regulator) and MKP1 (the negative regulator), which may contribute to the induction of optimal immune responses. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction-associated steatotic liver disease (MASLD) has become one of the most prevalent liver diseases worldwide, and its occurrence is strongly associated with obesity, insulin resistance (IR), genetics, and metabolic stress. Ranging from simple fatty liver to metabolic dysfunction-associated steatohepatitis (MASH), even to severe complications such as liver fibrosis and advanced cirrhosis or hepatocellular carcinoma, the underlying mechanisms of MASLD progression are complex and involve multiple cellular mediators and related signaling pathways. Pattern recognition receptors (PRRs) from the innate immune system, including Toll-like receptors (TLRs), C-type lectin receptors (CLRs), NOD-like receptors (NLRs), RIG-like receptors (RLRs), and DNA receptors, have been demonstrated to potentially contribute to the pathogenesis for MASLD. Their signaling pathways can induce inflammation, mediate oxidative stress, and affect the gut microbiota balance, ultimately resulting in hepatic steatosis, inflammatory injury and fibrosis. Here we review the available literature regarding the involvement of PRR-associated signals in the pathogenic and clinical features of MASLD, in vitro and in animal models of MASLD. We also discuss the emerging targets from PRRs for drug developments that involved agent therapies intended to arrest or reverse disease progression, thus enabling the refinement of therapeutic targets that can accelerate drug development.

Abstract Schistosomiasis, the second largest parasitic disease in the world after malaria, poses a significant threat to human health and causes public health issues. The disease primarily affects populations in economically underdeveloped tropical regions, earning it the title of “neglected tropical disease”. Schistosomiasis is difficult to eradicate globally if medication alone is used. One of the essential elements of thorough schistosomiasis prevention and control is the management and disruption of the life cycle of intermediate host snails. The key approach to controlling the transmission of schistosomiasis is to control the intermediate hosts of the schistosome to disrupt its life cycle. We believe that approaching it from the perspective of the intermediate host’s immunity could be an environmentally friendly and potentially effective method. Currently, globally significant intermediate host snails for schistosomes include Oncomelania hupensis, Biomphalaria glabrata, and Bulinus truncatus. The immune interaction research between B. glabrata and Schistosoma mansoni has a history of several decades, and the complete genome sequencing of both B. glabrata and B. truncatus has been accomplished. We have summarized the immune-related factors and research progress primarily studied in B. glabrata and B. truncatus and compared them with several humoral immune factors that O. hupensis research focuses on: macrophage migration inhibitory factor (MIF), Toll-like receptors (TLRs), and thioredoxin (Trx). We believe that continued exploration of the immune interactions between O. hupensis and Schistosoma japonicum is valuable. This comparative analysis can provide some direction and clues for further in-depth research. Comparative immunological studies between them not only expand our understanding of the immune defense responses of snails that act as intermediaries for schistosomes but also facilitate the development of more comprehensive and integrated strategies for schistosomiasis prevention and control. Furthermore, it offers an excellent opportunity to study the immune system of gastropods and their co-evolution with pathogenic organisms. Graphical Abstract

Schistosomiasis, the second largest parasitic disease in the world after malaria, poses a significant threat to human health and causes public health issues. The disease primarily affects populations in economically underdeveloped tropical regions, earning it the title of "neglected tropical disease". Schistosomiasis is difficult to eradicate globally if medication alone is used. One of the essential elements of thorough schistosomiasis prevention and control is the management and disruption of the life cycle of intermediate host snails. The key approach to controlling the transmission of schistosomiasis is to control the intermediate hosts of the schistosome to disrupt its life cycle. We believe that approaching it from the perspective of the intermediate host's immunity could be an environmentally friendly and potentially effective method. Currently, globally significant intermediate host snails for schistosomes include Oncomelania hupensis, Biomphalaria glabrata, and Bulinus truncatus. The immune interaction research between B. glabrata and Schistosoma mansoni has a history of several decades, and the complete genome sequencing of both B. glabrata and B. truncatus has been accomplished. We have summarized the immune-related factors and research progress primarily studied in B. glabrata and B. truncatus and compared them with several humoral immune factors that O. hupensis research focuses on: macrophage migration inhibitory factor (MIF), Toll-like receptors (TLRs), and thioredoxin (Trx). We believe that continued exploration of the immune interactions between O. hupensis and Schistosoma japonicum is valuable. This comparative analysis can provide some direction and clues for further in-depth research. Comparative immunological studies between them not only expand our understanding of the immune defense responses of snails that act as intermediaries for schistosomes but also facilitate the development of more comprehensive and integrated strategies for schistosomiasis prevention and control. Furthermore, it offers an excellent opportunity to study the immune system of gastropods and their co-evolution with pathogenic organisms. [ABSTRACT FROM AUTHOR]

Inflammatory responses by the innate and adaptive immune systems protect against infections and are essential to health and survival. Many diseases including atherosclerosis, osteoarthritis, rheumatoid arthritis, psoriasis, and obesity involve persistent chronic inflammation. Currently available anti-inflammatory agents, including non-steroidal anti-inflammatory drugs, steroids, and biologics, are often unsafe for chronic use due to adverse effects. The development of effective non-toxic anti-inflammatory agents for chronic use remains an important research arena. We previously reported that oral administration of Oxy210, a semi-synthetic oxysterol, ameliorates non-alcoholic steatohepatitis (NASH) induced by a high-fat diet in APOE*3-Leiden.CETP humanized mouse model of NASH and inhibits expression of hepatic and circulating levels of inflammatory cytokines. Here, we show that Oxy210 also inhibits diet-induced white adipose tissue inflammation in APOE*3-Leiden.CETP mice, evidenced by the inhibition of adipose tissue expression of IL-6, MCP-1, and CD68 macrophage marker. Oxy210 and related analogs exhibit anti-inflammatory effects in macrophages treated with lipopolysaccharide in vitro, mediated through inhibition of toll-like receptor 4 (TLR4), TLR2, and AP-1 signaling, independent of cyclooxygenase enzymes or steroid receptors. The anti-inflammatory effects of Oxy210 are correlated with the inhibition of macrophage polarization. We propose that Oxy210 and its structural analogs may be attractive candidates for future therapeutic development for targeting inflammatory diseases.

Previous studies reported the expression of toll-like receptors (TLRs), merely TLR2 and TLR4, and complement fragments (C3a, C5b9) in vitreoretinal disorders. Other than pathogens, TLRs can recognize endogenous products of tissue remodeling as damage-associated molecular pattern (DAMPs). The aim of this study was to confirm the expression of TLR2 and TLR4 in the fibrocellular membranes and vitreal fluids (soluble TLRs) of patients suffering of epiretinal membranes (ERMs) and assess their association with disease severity, complement fragments and inflammatory profiles. Twenty (n = 20) ERMs and twelve (n = 12) vitreous samples were collected at the time of the vitrectomy. Different severity-staged ERMs were processed for: immunolocalization (IF), transcriptomic (RT-PCR) and proteomics (ELISA, IP/WB, Protein Chip Array) analysis. The investigation of targets included TLR2, TLR4, C3a, C5b9, a few selected inflammatory biomarkers (Eotaxin-2, Rantes, Vascular Endothelial Growth Factor (VEGFA), Vascular Endothelial Growth Factor receptor (VEGFR2), Interferon-γ (IFNγ), Interleukin (IL1β, IL12p40/p70)) and a restricted panel of matrix enzymes (Matrix metalloproteinases (MMPs)/Tissue Inhibitor of Metallo-Proteinases (TIMPs)). A reduced cellularity was observed as function of ERM severity. TLR2, TLR4 and myD88 transcripts/proteins were detected in membranes and decreased upon disease severity. The levels of soluble TLR2 and TLR4, as well as C3a, C5b9, Eotaxin-2, Rantes, VEGFA, VEGFR2, IFNγ, IL1β, IL12p40/p70, MMP7 and TIMP2 levels were changed in vitreal samples. Significant correlations were observed between TLRs and complement fragments and between TLRs and some inflammatory mediators. Our findings pointed at TLR2 and TLR4 over-expression at early stages of ERM formation, suggesting the participation of the local immune response in the severity of disease. These activations at the early-stage of ERM formation suggest a potential persistence of innate immune response in the early phases of fibrocellular membrane formation.

Background :otitis media is considered the more diseases common spread related hearing loss ,This study is designed to focus on TLR4 expression that stimulating result presence LPS in otitis media Objective :detect the genotype more infection in otitis media on blood patients sample expression in PCR Technical. Methods :The current study blood specimens we get of 50 patient and chronic Otitis media and 50 blood samples from healthy people to Extracting and dissection of the DNA blood gram negative bacteria and evaluate the mechanical and work of LPS and its effect on Toll like receptor4. Results :The results show most patients with P. arogenosia isolates have GG genotype 9 in comparison with other genotype AG, 15 and AA 26 and control group show GG genotype 4 in comparison with other genotype AG 11, and AA 36 . Conclusions: The study is showed a high rate of chronic otitis media in patients with the GG genotype, suggesting that this genotype may be a risk factor compared to the control group. On the other hand, the AA genotype was found to be ӏow in patients but high in the control group, indicating a possible is protected factor.

The canonical NOD-like receptor family pyrin domain containing 3 (NLRP3) pathway involves a priming step to induce pro-IL-1β followed by a secondary signal such as K+ efflux to activate inflammasome formation. This then leads to the maturation of IL-1β and the formation of gasdermin D (GSDMD) pores that initiate pyroptosis and mediate IL-1β release. In contrast, primary human monocytes also engage an alternative pathway in response to toll-like receptor (TLR) 4 activation, without the need for a secondary signal. Data from a monocyte-like cell line suggest that the alternative pathway functions via the TLR adaptor protein TIR-domain-containing adapter-inducing interferon-b (TRIF), receptor-interacting protein kinase 1 (RIPK1), FAS-associated death domain (FADD) and caspase-8 upstream of NLRP3 activation, but in the absence of K+ efflux or pyroptosis. Usage of the alternative pathway by other members of the TLR family that induce IL-1β but do not signal through TRIF, has yet to be explored in primary human monocytes. Furthermore, the mechanism by which IL-1β is released from monocytes remains unclear. Therefore, this study investigated if the alternative NLRP3 inflammasome pathway is initiated following activation of TLRs other than TLR4, and if GSDMD was necessary for the release of IL-1β. Monocytes were stimulated with ligands that activate TLR1/2, TLR2/6, TLR4 and TLR7 and/or TLR8 (using a dual ligand). Similar to TLR4, all of the TLRs investigated induced IL-1β release in a NLRP3 and caspase-1 dependent manner, indicating that TRIF may not be an essential upstream component of the alternative pathway. Furthermore, inhibition of RIPK1 kinase activity had no effect on IL-1β release. Although IL-1β was released independently of K+ efflux and pyroptosis, it was significantly reduced by an inhibitor of GSDMD. Therefore, it is feasible that low level GSDMD pore formation may facilitate the release of IL-1β from the cell, but not be present in sufficient quantities to initiate pyroptosis. Together these data suggest that the alternative pathway operates independently of RIPK1 kinase activity, downstream of diverse TLRs including TLR4 in primary human monocytes and supports the potential for IL-1β release via GSDMD pores alongside other unconventional secretory pathways. [ABSTRACT FROM AUTHOR]

Chronic Kidney Disease (CKD) is associated with markedly increased cardiovascular (CV) morbidity and mortality. Chronic inflammation, a hallmark of both CKD and CV diseases (CVD), is believed to drive this association. Pro-inflammatory endogenous TLR agonists, Damage-Associated Molecular Patterns (DAMPs), have been found elevated in CKD patients’ plasma and suggested to promote CVD, however, confirmation of their involvement, the underlying mechanism(s), the extent to which individual DAMPs contribute to vascular pathology in CKD and the evaluation of potential therapeutic strategies, have remained largely undescribed. A multi-TLR inhibitor, soluble TLR2, abrogated chronic vascular inflammatory responses and the increased aortic atherosclerosis-associated gene expression observed in nephropathic mice, without compromising infection clearance. Mechanistically, we confirmed elevation of 4 TLR DAMPs in CKD patients’ plasma, namely Hsp70, Hyaluronic acid, HMGB-1 and Calprotectin, which displayed different abilities to promote key cellular responses associated with vascular inflammation and progression of atherosclerosis in a TLR-dependent manner. These included loss of trans-endothelial resistance, enhanced monocyte migration, increased cytokine production, and foam cell formation by macrophages, the latter via cholesterol efflux inhibition. Calprotectin and Hsp70 most consistently affected these functions. Calprotectin was further elevated in CVD-diagnosed CKD patients and strongly correlated with the predictor of CV events CRP. In nephropathic mice, Calprotectin blockade robustly reduced vascular chronic inflammatory responses and pro-atherosclerotic gene expression in the blood and aorta. Taken together, these findings demonstrated the critical extent to which the DAMP-TLR pathway contributes to vascular inflammatory and atherogenic responses in CKD, revealed the mechanistic contribution of specific DAMPs and described two alternatives therapeutic approaches to reduce chronic vascular inflammation and lower CV pathology in CKD. [ABSTRACT FROM AUTHOR]

Toll-like receptors (TLRs) serve as the body's first line of defense, recognizing both pathogen-expressed molecules and host-derived molecules released from damaged or dying cells. The wide distribution of different cell types, ranging from epithelial to immune cells, highlights the crucial roles of TLRs in linking innate and adaptive immunity. Upon stimulation, TLRs binding mediates the expression of several adapter proteins and downstream kinases, that lead to the induction of several other signaling molecules such as key pro-inflammatory mediators. Indeed, extraordinary progress in immunobiological research has suggested that TLRs could represent promising targets for the therapeutic intervention of inflammation-associated diseases, autoimmune diseases, microbial infections as well as human cancers. So far, for the prevention and possible treatment of inflammatory diseases, various TLR antagonists/inhibitors have shown to be efficacious at several stages from pre-clinical evaluation to clinical trials. Therefore, the fascinating role of TLRs in modulating the human immune responses at innate as well as adaptive levels directed the scientists to opt for these immune sensor proteins as suitable targets for developing chemotherapeutics and immunotherapeutics against cancer. Hitherto, several TLR-targeting small molecules (e.g., Pam3CSK4, Poly (I:C), Poly (A:U)), chemical compounds, phytocompounds (e.g., Curcumin), peptides, and antibodies have been found to confer protection against several types of cancers. However, administration of inappropriate doses of such TLR-modulating therapeutics or a wrong infusion administration is reported to induce detrimental outcomes. This review summarizes the current findings on the molecular and structural biology of TLRs and gives an overview of the potency and promises of TLR-directed therapeutic strategies against cancers by discussing the findings from established and pipeline discoveries. [ABSTRACT FROM AUTHOR]

Otitis media is considered the more diseases commonly spread related to hearing loss, This study is designed to focus on TLR4 expression that stimulates the result presence of LPS in otitis media. To detect the genotype of more infection in otitis media on blood patient's sample expression in PCR Technical. In the current study blood specimens we get of 50 patients and chronic Otitis media and 50 blood samples from healthy people to Extract and dissection of the DNA blood gram-negative bacteria and evaluate the mechanical work of LPS and its effect on Toll like receptor4. The results show most patients with P. arogenosia isolates have GG genotype 9 in comparison with another genotype AG, 15 and AA 26 and the control group show GG genotype 4 in comparison with other genotype AG 11, and AA 36. The study is showed a high rate of chronic otitis media in patients with the GG genotype, suggesting that this genotype may be a risk factor compared to the control group. On the other hand, the AA genotype was found to be low in patients but high in the control group, indicating a possible is protected factor [ABSTRACT FROM AUTHOR]

Toll-like receptors (TLRs) induce innate immune responses through activation of intracellular signaling pathways, such as MAP kinase and NF-κB signaling pathways, and play an important role in host defense against bacterial or viral infections. Meanwhile, excessive activation of TLR signaling leads to a variety of inflammatory disorders, including autoimmune diseases. TLR signaling is therefore strictly controlled to balance optimal immune response and inflammation. However, its balancing mechanisms are not fully understood. In this study, we identified the E3 ubiquitin ligase LINCR/ NEURL3 as a critical regulator of TLR signaling. In LINCR-deficient cells, the sustained activation of JNK and p38 MAPKs induced by the agonists for TLR3, TLR4, and TLR5, was clearly attenuated. Consistent with these observations, TLR-induced production of a series of inflammatory cytokines was significantly attenuated, suggesting that LINCR positively regulates innate immune responses by promoting the activation of JNK and p38. Interestingly, our further mechanistic study identified MAPK phosphatase-1 (MKP1), a negative regulator of MAP kinases, as a ubiquitination target of LINCR. Thus, our results demonstrate that TLRs fine-tune the activation of MAP kinase pathways by balancing LINCR (the positive regulator) and MKP1 (the negative regulator), which may contribute to the induction of optimal immune responses.

The canonical NOD-like receptor family pyrin domain containing 3 (NLRP3) pathway involves a priming step to induce pro-IL-1β followed by a secondary signal such as K+ efflux to activate inflammasome formation. This then leads to the maturation of IL-1β and the formation of gasdermin D (GSDMD) pores that initiate pyroptosis and mediate IL-1β release. In contrast, primary human monocytes also engage an alternative pathway in response to toll-like receptor (TLR) 4 activation, without the need for a secondary signal. Data from a monocyte-like cell line suggest that the alternative pathway functions via the TLR adaptor protein TIR-domain-containing adapter-inducing interferon-β (TRIF), receptor-interacting protein kinase 1 (RIPK1), FAS-associated death domain (FADD) and caspase-8 upstream of NLRP3 activation, but in the absence of K+ efflux or pyroptosis. Usage of the alternative pathway by other members of the TLR family that induce IL-1β but do not signal through TRIF, has yet to be explored in primary human monocytes. Furthermore, the mechanism by which IL-1β is released from monocytes remains unclear. Therefore, this study investigated if the alternative NLRP3 inflammasome pathway is initiated following activation of TLRs other than TLR4, and if GSDMD was necessary for the release of IL-1β. Monocytes were stimulated with ligands that activate TLR1/2, TLR2/6, TLR4 and TLR7 and/or TLR8 (using a dual ligand). Similar to TLR4, all of the TLRs investigated induced IL-1β release in a NLRP3 and caspase-1 dependent manner, indicating that TRIF may not be an essential upstream component of the alternative pathway. Furthermore, inhibition of RIPK1 kinase activity had no effect on IL-1β release. Although IL-1β was released independently of K+ efflux and pyroptosis, it was significantly reduced by an inhibitor of GSDMD. Therefore, it is feasible that low level GSDMD pore formation may facilitate the release of IL-1β from the cell, but not be present in sufficient quantities to initiate pyroptosis. Together these data suggest that the alternative pathway operates independently of RIPK1 kinase activity, downstream of diverse TLRs including TLR4 in primary human monocytes and supports the potential for IL-1β release via GSDMD pores alongside other unconventional secretory pathways.

Chronic Kidney Disease (CKD) is associated with markedly increased cardiovascular (CV) morbidity and mortality. Chronic inflammation, a hallmark of both CKD and CV diseases (CVD), is believed to drive this association. Pro-inflammatory endogenous TLR agonists, Damage-Associated Molecular Patterns (DAMPs), have been found elevated in CKD patients’ plasma and suggested to promote CVD, however, confirmation of their involvement, the underlying mechanism(s), the extent to which individual DAMPs contribute to vascular pathology in CKD and the evaluation of potential therapeutic strategies, have remained largely undescribed. A multi-TLR inhibitor, soluble TLR2, abrogated chronic vascular inflammatory responses and the increased aortic atherosclerosis-associated gene expression observed in nephropathic mice, without compromising infection clearance. Mechanistically, we confirmed elevation of 4 TLR DAMPs in CKD patients’ plasma, namely Hsp70, Hyaluronic acid, HMGB-1 and Calprotectin, which displayed different abilities to promote key cellular responses associated with vascular inflammation and progression of atherosclerosis in a TLR-dependent manner. These included loss of trans-endothelial resistance, enhanced monocyte migration, increased cytokine production, and foam cell formation by macrophages, the latter via cholesterol efflux inhibition. Calprotectin and Hsp70 most consistently affected these functions. Calprotectin was further elevated in CVD-diagnosed CKD patients and strongly correlated with the predictor of CV events CRP. In nephropathic mice, Calprotectin blockade robustly reduced vascular chronic inflammatory responses and pro-atherosclerotic gene expression in the blood and aorta. Taken together, these findings demonstrated the critical extent to which the DAMP-TLR pathway contributes to vascular inflammatory and atherogenic responses in CKD, revealed the mechanistic contribution of specific DAMPs and described two alternatives therapeutic approaches to reduce chronic vascular inflammation and lower CV pathology in CKD.

Toll-like receptors (TLRs) serve as the body’s first line of defense, recognizing both pathogen-expressed molecules and host-derived molecules released from damaged or dying cells. The wide distribution of different cell types, ranging from epithelial to immune cells, highlights the crucial roles of TLRs in linking innate and adaptive immunity. Upon stimulation, TLRs binding mediates the expression of several adapter proteins and downstream kinases, that lead to the induction of several other signaling molecules such as key pro-inflammatory mediators. Indeed, extraordinary progress in immunobiological research has suggested that TLRs could represent promising targets for the therapeutic intervention of inflammation-associated diseases, autoimmune diseases, microbial infections as well as human cancers. So far, for the prevention and possible treatment of inflammatory diseases, various TLR antagonists/inhibitors have shown to be efficacious at several stages from pre-clinical evaluation to clinical trials. Therefore, the fascinating role of TLRs in modulating the human immune responses at innate as well as adaptive levels directed the scientists to opt for these immune sensor proteins as suitable targets for developing chemotherapeutics and immunotherapeutics against cancer. Hitherto, several TLR-targeting small molecules (e.g., Pam3CSK4, Poly (I:C), Poly (A:U)), chemical compounds, phytocompounds (e.g., Curcumin), peptides, and antibodies have been found to confer protection against several types of cancers. However, administration of inappropriate doses of such TLR-modulating therapeutics or a wrong infusion administration is reported to induce detrimental outcomes. This review summarizes the current findings on the molecular and structural biology of TLRs and gives an overview of the potency and promises of TLR-directed therapeutic strategies against cancers by discussing the findings from established and pipeline discoveries.

More than 50% of all people living with HIV worldwide are women. Globally, HIV/AIDS is the leading cause of death among women aged 15 to 44. The safe and effective methods of hormonal contraception are an essential component of preventive medical care in order to reduce maternal and infant mortality. However, there is limited knowledge regarding the effect of hormones on the rate of viral replication in HIV infection, especially non-B subtypes. The goal of the present work was to study in vitro how the female hormones β-estradiol and progesterone affect the replication of the HIV-1 subtypes A6, CRF02_AG, and B. The findings show that high doses of hormones enhanced the replication of HIV-1 sub-subtype A6 by an average of 1.75 times and the recombinant variant CRF02_AG by 1.4 times but did not affect the replication of HIV-1 subtype B. No difference was detected in the expression of CCR5 and CXCR4 co-receptors on the cell surface, either in the presence or absence of hormones. However, one of the reasons for the increased viral replication could be the modulated TLRs secretion, as it was found that high doses of estradiol and progesterone upregulated, to varying degrees, the expression of TLR2 and TLR9 genes in the PBMCs of female donors infected with HIV-1 sub-subtype A6. [ABSTRACT FROM AUTHOR]

Abstract Toll-like receptors (TLRs) are a large family of proteins that are expressed in immune cells and various tumor cells. TLR7/8 are located in the intracellular endosomes, participate in tumor immune surveillance and play different roles in tumor growth. Activation of TLRs 7 and 8 triggers induction of a Th1 type innate immune response in the highly sophisticated process of innate immunity signaling with the recent research advances involving the small molecule activation of TLR 7 and 8. The wide range of expression and clinical significance of TLR7/TLR8 in different kinds of cancers have been extensively explored. TLR7/TLR8 can be used as novel diagnostic biomarkers, progression and prognostic indicators, and immunotherapeutic targets for various tumors. Although the mechanism of action of TLR7/8 in cancer immunotherapy is still incomplete, TLRs on T cells are involved in the regulation of T cell function and serve as co-stimulatory molecules and activate T cell immunity. TLR agonists can activate T cell-mediated antitumor responses with both innate and adaptive immune responses to improve tumor therapy. Recently, novel drugs of TLR7 or TLR8 agonists with different scaffolds have been developed. These agonists lead to the induction of certain cytokines and chemokines that can be applied to the treatment of some diseases and can be used as good adjutants for vaccines. Furthermore, TLR7/8 agonists as potential therapeutics for tumor-targeted immunotherapy have been developed. In this review, we summarize the recent advances in the development of immunotherapy strategies targeting TLR7/8 in patients with various cancers and chronic hepatitis B.

Background Toll-like receptors (TLRs) are important components of the innate and adaptive immune systems, and abnormal TLR expression has been linked to a variety of cancers. However, there was a lack of clarity on the association of TLR stimulation with the carcinogenesis of cancer. The study's goal was to analyse the clinical importance of TLRs expression at the mRNA level in pan-cancer datasets, as well as the link between TLR expression and carcinogenesis, progression, and clinical prognosis.Methods The expression profile of TLRs derived from UCSC pan-cancer data was analysed in multiple dimensions, including clinical analysis, immunological subtype analysis, tumour microenvironment (TME) analysis, tumour stem cell correlation analysis, and drug sensitivity analysis. Additionally, we analyse protein-protein interactions, functional enrichment, and chromatin accessibility, as well as TLR expression in single-cell sequencing data.Results Our multi-omics analysis results imply that TLRs may operate as a biological marker for carcinogenesis and progression, a potential target for anti-tumour therapy, and a prognostic biomarker, laying the theoretical groundwork for future translational medicine research.Conclusion TLRs are involved in the formation of malignancies and can be explored in further detail as potential prognostic indicators. Key MessagesToll-like receptors (TLRs) are key factors in the process of the innate and adaptive immune response, and their aberrant expression of TLRs have been widely reported in various cancer. However, the association between TLRs stimulation and tumorigenesis of cancer has not been well clarified.In this study, in the pan-cancer data, integrated TLR family gene expression analysis, clinical correlation analysis, immune subtype correlation analysis, tumour microenvironment correlation analysis, tumour stem cell correlation analysis, and drug sensitivity correlation analysis were performed.TLRs play an important role in the development of tumours and can be studied in depth as potential prognostic markers.

The clinical manifestations of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection responsible for coronavirus disease 2019 (COVID-19) commonly include dyspnoea and fatigue, and they primarily involve the lungs. However, extra-pulmonary organ dysfunctions, particularly affecting the cardiovascular system, have also been observed following COVID-19 infection. In this context, several cardiac complications have been reported, including hypertension, thromboembolism, arrythmia and heart failure, with myocardial injury and myocarditis being the most frequent. These secondary myocardial inflammatory responses appear to be associated with a poorer disease course and increased mortality in patients with severe COVID-19. In addition, numerous episodes of myocarditis have been reported as a complication of COVID-19 mRNA vaccinations, especially in young adult males. Changes in the cell surface expression of angiotensin-converting enzyme 2 (ACE2) and direct injury to cardiomyocytes resulting from exaggerated immune responses to COVID-19 are just some of the mechanisms that may explain the pathogenesis of COVID-19-induced myocarditis. Here, we review the pathophysiological mechanisms underlying myocarditis associated with COVID-19 infection, with a particular focus on the involvement of ACE2 and Toll-like receptors (TLRs). [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is one of the most common cancers and is the second-highest in cancer-related deaths worldwide. The changes in gut homeostasis and microbial dysbiosis lead to the initiation of the tumorigenesis process. Several pathogenic gram-negative bacteria including Fusobacterium nucleatum are the principal contributors to the induction and pathogenesis of CRC. Thus, inhibiting the growth and survival of these pathogens can be a useful intervention strategy. Fibroblast activation protein-2 (Fap2) is an essential membrane protein of F. nucleatum that promotes the adherence of the bacterium to the colon cells, recruitment of immune cells, and induction of tumorigenesis. The present study depicts the design of an in silico vaccine candidate comprising the B-cell and T-cell epitopes of Fap2 for improving cell-mediated and humoral immune responses against CRC. Notably, this vaccine participates in significant protein–protein interactions with human Toll-like receptors, especially with TLR6 reveals, which is most likely to be correlated with its efficacy in eliciting potential immune responses. The immunogenic trait of the designed vaccine was verified by immune simulation approach. The cDNA of the vaccine construct was cloned in silico within the expression vector pET30ax for protein expression. Collectively, the proposed vaccine construct may serve as a promising therapeutic in intervening F. nucleatum-induced human CRC. [ABSTRACT FROM AUTHOR]

Toll-like receptors (TLRs), as a family of pattern recognition receptors, play an important role in the recognition of HIV-1 molecular structures by various cells of the innate immune system, but also provide a functional association with subsequent mechanisms of adaptive immunity. TLR7 and TLR8 play a particularly important role in the innate immune response to RNA viruses due to their ability to recognise GU-rich single-stranded RNA molecules and subsequently activate intracellular signalling pathways resulting in expression of genes coding for various biological response modifiers (interferons, proinflammatory cytokines, chemokines). The aim of this review is to summarise the most recent knowledge on the role of TLRs in the innate immune response to HIV-1 and the role of TLR gene polymorphisms in the biology and in the clinical aspects of HIV infections. In addition, the role of TLR agonists as latency reversing agents in research to treat HIV infections and as immunomodulators in HIV vaccine research will be discussed. [ABSTRACT FROM AUTHOR]

Toll-like receptors (TLRs) are a large family of proteins that are expressed in immune cells and various tumor cells. TLR7/8 are located in the intracellular endosomes, participate in tumor immune surveillance and play different roles in tumor growth. Activation of TLRs 7 and 8 triggers induction of a Th1 type innate immune response in the highly sophisticated process of innate immunity signaling with the recent research advances involving the small molecule activation of TLR 7 and 8. The wide range of expression and clinical significance of TLR7/TLR8 in different kinds of cancers have been extensively explored. TLR7/TLR8 can be used as novel diagnostic biomarkers, progression and prognostic indicators, and immunotherapeutic targets for various tumors. Although the mechanism of action of TLR7/8 in cancer immunotherapy is still incomplete, TLRs on T cells are involved in the regulation of T cell function and serve as co-stimulatory molecules and activate T cell immunity. TLR agonists can activate T cell-mediated antitumor responses with both innate and adaptive immune responses to improve tumor therapy. Recently, novel drugs of TLR7 or TLR8 agonists with different scaffolds have been developed. These agonists lead to the induction of certain cytokines and chemokines that can be applied to the treatment of some diseases and can be used as good adjutants for vaccines. Furthermore, TLR7/8 agonists as potential therapeutics for tumor-targeted immunotherapy have been developed. In this review, we summarize the recent advances in the development of immunotherapy strategies targeting TLR7/8 in patients with various cancers and chronic hepatitis B. [ABSTRACT FROM AUTHOR]

Toll-like receptors (TLRs) are important components of the innate and adaptive immune systems, and abnormal TLR expression has been linked to a variety of cancers. However, there was a lack of clarity on the association of TLR stimulation with the carcinogenesis of cancer. The study's goal was to analyse the clinical importance of TLRs expression at the mRNA level in pan-cancer datasets, as well as the link between TLR expression and carcinogenesis, progression, and clinical prognosis. The expression profile of TLRs derived from UCSC pan-cancer data was analysed in multiple dimensions, including clinical analysis, immunological subtype analysis, tumour microenvironment (TME) analysis, tumour stem cell correlation analysis, and drug sensitivity analysis. Additionally, we analyse protein-protein interactions, functional enrichment, and chromatin accessibility, as well as TLR expression in single-cell sequencing data. Our multi-omics analysis results imply that TLRs may operate as a biological marker for carcinogenesis and progression, a potential target for anti-tumour therapy, and a prognostic biomarker, laying the theoretical groundwork for future translational medicine research. TLRs are involved in the formation of malignancies and can be explored in further detail as potential prognostic indicators. Toll-like receptors (TLRs) are key factors in the process of the innate and adaptive immune response, and their aberrant expression of TLRs have been widely reported in various cancer. However, the association between TLRs stimulation and tumorigenesis of cancer has not been well clarified. In this study, in the pan-cancer data, integrated TLR family gene expression analysis, clinical correlation analysis, immune subtype correlation analysis, tumour microenvironment correlation analysis, tumour stem cell correlation analysis, and drug sensitivity correlation analysis were performed. TLRs play an important role in the development of tumours and can be studied in depth as potential prognostic markers. [ABSTRACT FROM AUTHOR]

ABSTRACT Transposable elements (TEs) are mobile genomic sequences that encompass roughly 50% of the human genome. Class 1 TEs, or “retrotransposons,” mobilize through the production of an RNA intermediate that is then reverse transcribed to form complementary DNA (cDNA) molecules capable of genomic reinsertion. While TEs are traditionally silenced to maintain genomic integrity, the recognition of immunostimulatory cues, such as those provided by microorganisms, drastically alters host transcription to induce the differential expression of TEs. Emerging evidence demonstrates that the inducible production of TE cDNA is not an inert phenomenon but instead has been coopted by host immunity to facilitate cross talk between host and constituents of the microbiota by agonizing intrinsic antiviral receptors. Here, we demonstrate that immunostimulation of toll-like receptor 4 (TLR4) with lipopolysaccharide (LPS) and TLR5 with bacterial flagella (FLA) alters the expression of retrotransposons, such as human endogenous retroviruses (HERVs) and long interspersed nuclear elements (LINEs). Next, we demonstrate that reverse transcriptase inhibitor (RTi) delivery ameliorates the acute production of the proinflammatory cytokine “tumor necrosis factor alpha” (TNF-α) in response to FLA in a monocytic cell line (THP-1). Collectively, our findings demonstrate that TLR5-mediated cross talk between the host and microbiota is partially dependent on the reverse transcription (RT) of retrotransposons. IMPORTANCE The microbiota is a potent reservoir of immunostimulatory and immunosuppressive motifs that fundamentally shape host immunity. Despite broad associations between microbial composition and host immunity, the mechanisms underlying host microbiota-induced immunoregulation remain poorly defined. Here, we demonstrate a novel mechanism by which motifs overabundant during dysbiotic conditions influence host immunity through the upregulation of endogenous RT to produce motifs that agonize antiviral receptors.

In 2011, the Nobel Prize in Physiology or Medicine was awarded to three immunologists: Bruce A. Beutler, Jules A. Hoffmann, and Ralph M. Steinman. While Steinman was honored for his work on dendritic cells and adaptive immunity, Beutler and Hoffman received the prize for their contributions to discoveries in innate immunity. In 1996, Hoffmann found the toll gene to be crucial for mounting antimicrobial responses in fruit flies, first implicating this developmental gene in immune signaling. Two years later, Beutler built on this observation by describing a Toll-like gene, tlr4, as the receptor for the bacterial product LPS, representing a crucial step in innate immune activation and protection from bacterial infections in mammals. These publications spearheaded research in innate immune sensing and sparked a huge interest regarding innate defense mechanisms in the following years and decades. Today, Beutler and Hoffmann's research has not only resulted in the discovery of the role of multiple TLRs in innate immunity but also in a much broader understanding of the molecular components of the innate immune system. In this review, we aim to collect the discoveries leading up to the publications of Beutler and Hoffmann, taking a close look at how early advances in both developmental biology and immunology converged into the research awarded with the Nobel Prize. We will also discuss how these discoveries influenced future research and highlight the importance they hold today. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) is a high incident rate of central nervous system disease that usually causes paralysis below the injured level. The occurrence of chronic inflammation with the axonal regeneration difficulties are the underlying barriers for the recovery of SCI patients. Current studies have paid attention to controlling the instigative and developmental process of neuro-inflammation. Ethyl pyruvate, as a derivative of pyruvate, has strong anti-inflammatory and neuroprotective functions. Herein, we reviewed the recent studies of ethyl pyruvate and high mobility group box-1 (HMGB1). We think HMGB1 that is one of the main nuclear protein mediators to cause an inflammatory response. This protein induces astrocytic activation, and promotes glial scar formation. Interestingly, ethyl pyruvate has potent inhibitory effects on HMGB1 protein, as it inhibits chronic inflammatory response by modulating the HMGB1/TLR4/NF-kB signaling pathway. This paper discusses the potential mechanism of ethyl pyruvate in inhibiting chronic inflammation after SCI. Ethyl pyruvate can be a prospective therapeutic agent for SCI. [ABSTRACT FROM AUTHOR]

More than 50% of all people living with HIV worldwide are women. Globally, HIV/AIDS is the leading cause of death among women aged 15 to 44. The safe and effective methods of hormonal contraception are an essential component of preventive medical care in order to reduce maternal and infant mortality. However, there is limited knowledge regarding the effect of hormones on the rate of viral replication in HIV infection, especially non-B subtypes. The goal of the present work was to study in vitro how the female hormones β-estradiol and progesterone affect the replication of the HIV-1 subtypes A6, CRF02_AG, and B. The findings show that high doses of hormones enhanced the replication of HIV-1 sub-subtype A6 by an average of 1.75 times and the recombinant variant CRF02_AG by 1.4 times but did not affect the replication of HIV-1 subtype B. No difference was detected in the expression of CCR5 and CXCR4 co-receptors on the cell surface, either in the presence or absence of hormones. However, one of the reasons for the increased viral replication could be the modulated TLRs secretion, as it was found that high doses of estradiol and progesterone upregulated, to varying degrees, the expression of TLR2 and TLR9 genes in the PBMCs of female donors infected with HIV-1 sub-subtype A6.

Inflammatory cytokines, cell adhesion molecules, and toll-like receptors (TLRs) play an important role in atherosclerosis. The aim of this study was to further evaluate the role of inflammatory cytokines, cell adhesion molecules, and toll-like receptors in atherosclerosis. Forty local breed domestic male rabbits were divided randomly into 4 groups, 10 rabbits each. Group I was the control group, group II received a high cholesterol diet, group III received the drug solvent dimethyl sulfoxide (DMSO), and group IV received Atorvastatin (3.5 mg/kg/day). Blood samples were collected at 0 times, 5 weeks, and at the end of 10 weeks. TLRs expression on monocyte was measured by flow cytometry, IL-10, IL-17, IL-1ß, intracellular adhesion molecule (ICAM), and vascular cell adhesion molecule (VCAM) were measured by ELISA. In group II, a high cholesterol diet led to a statistically significant elevation of lipids profile (TC, TG, and LDL) at both 5 weeks and 10 weeks compared to the control. The expression of TLRs was also increased compared to the control (13.53±2.5 to 25.79±6.5). The intimal thickness increased from 103.46±13.85 to 248.43±11.11. IL-17 increased significantly from 3.4±0.4 to 7.7±1.00, and IL-1ß increased from 1.04±0.19 to 9.66±1.4 (P 0.05) at 10 weeks. ICAM and VCAM increased from 1.7±0.16 to 8.2±0.74 and from 0.89±0.07 to 5.2±0.45, respectively. Atorvastatin significantly reduced TLRs at 10 weeks to 21.98±3.4 and intimal thickness to 191.6±15.59. IL-17, IL-1ß, ICAM, and VCAM were significantly reduced by Atorvastatin. Cytokines, cellular adhesion molecules, and probably TLRs have a role in the pathogenesis of hyperlipidemia and atherosclerosis. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction-associated steatotic liver disease (MASLD) has become one of the most prevalent liver diseases worldwide, and its occurrence is strongly associated with obesity, insulin resistance (IR), genetics, and metabolic stress. Ranging from simple fatty liver to metabolic dysfunction-associated steatohepatitis (MASH), even to severe complications such as liver fibrosis and advanced cirrhosis or hepatocellular carcinoma, the underlying mechanisms of MASLD progression are complex and involve multiple cellular mediators and related signaling pathways. Pattern recognition receptors (PRRs) from the innate immune system, including Toll-like receptors (TLRs), C-type lectin receptors (CLRs), NOD-like receptors (NLRs), RIG-like receptors (RLRs), and DNA receptors, have been demonstrated to potentially contribute to the pathogenesis for MASLD. Their signaling pathways can induce inflammation, mediate oxidative stress, and affect the gut microbiota balance, ultimately resulting in hepatic steatosis, inflammatory injury and fibrosis. Here we review the available literature regarding the involvement of PRR-associated signals in the pathogenic and clinical features of MASLD, in vitro and in animal models of MASLD. We also discuss the emerging targets from PRRs for drug developments that involved agent therapies intended to arrest or reverse disease progression, thus enabling the refinement of therapeutic targets that can accelerate drug development. [Display omitted] • PRR signaling is contributed to the pathogenesis for MAFLD. • TLRs、CLRs、NLRs、RLRs and DNA receptors are family members of PRR that involved in the occurrence of liver-related diseases. • The design of drugs targeting the PRR signaling system has show the potential therapeutic effects in the prevention and treatment of MASLD. [ABSTRACT FROM AUTHOR]

The clinical manifestations of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection responsible for coronavirus disease 2019 (COVID-19) commonly include dyspnoea and fatigue, and they primarily involve the lungs. However, extra-pulmonary organ dysfunctions, particularly affecting the cardiovascular system, have also been observed following COVID-19 infection. In this context, several cardiac complications have been reported, including hypertension, thromboembolism, arrythmia and heart failure, with myocardial injury and myocarditis being the most frequent. These secondary myocardial inflammatory responses appear to be associated with a poorer disease course and increased mortality in patients with severe COVID-19. In addition, numerous episodes of myocarditis have been reported as a complication of COVID-19 mRNA vaccinations, especially in young adult males. Changes in the cell surface expression of angiotensin-converting enzyme 2 (ACE2) and direct injury to cardiomyocytes resulting from exaggerated immune responses to COVID-19 are just some of the mechanisms that may explain the pathogenesis of COVID-19-induced myocarditis. Here, we review the pathophysiological mechanisms underlying myocarditis associated with COVID-19 infection, with a particular focus on the involvement of ACE2 and Toll-like receptors (TLRs).

Background. Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections have become increasingly severe worldwide and are a threat to public health. There have been a number of studies conducted recently on the relationship of single nucleotide polymorphisms (SNPs) to innate immune receptor genes such as toll-like receptors (TLRs). Some literature suggests that SNPs of TLRs are associated with HBV and HCV infection. We summarized the role of TLRs gene polymorphisms associated with HBV and HCV infections and explored their possible mechanisms of action. Methodology. PubMed and Web of Science were used to perform the literature review. Related articles and references were identified and used to analyze the role of TLRs gene polymorphism in HBV and HCV infection. Results. TLRs gene polymorphisms may have beneficial or detrimental effects in HBV and HCV infection, and some SNPs can affect disease progression or prognosis. They affect the disease state by altering gene expression or protein synthesis; however, the mechanism of action is not clearly understood. Conclusions. Single nucleotide polymorphisms of TLRs play a role in HBV and HCV infection, but the mechanism of action still needs to be explored in future studies. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is one of the most common cancers and is the second-highest in cancer-related deaths worldwide. The changes in gut homeostasis and microbial dysbiosis lead to the initiation of the tumorigenesis process. Several pathogenic gram-negative bacteria including Fusobacterium nucleatum are the principal contributors to the induction and pathogenesis of CRC. Thus, inhibiting the growth and survival of these pathogens can be a useful intervention strategy. Fibroblast activation protein-2 (Fap2) is an essential membrane protein of F. nucleatum that promotes the adherence of the bacterium to the colon cells, recruitment of immune cells, and induction of tumorigenesis. The present study depicts the design of an in silico vaccine candidate comprising the B-cell and T-cell epitopes of Fap2 for improving cell-mediated and humoral immune responses against CRC. Notably, this vaccine participates in significant protein–protein interactions with human Toll-like receptors, especially with TLR6 reveals, which is most likely to be correlated with its efficacy in eliciting potential immune responses. The immunogenic trait of the designed vaccine was verified by immune simulation approach. The cDNA of the vaccine construct was cloned in silico within the expression vector pET30ax for protein expression. Collectively, the proposed vaccine construct may serve as a promising therapeutic in intervening F. nucleatum-induced human CRC.

Toll-like receptors (TLRs), as a family of pattern recognition receptors, play an important role in the recognition of HIV-1 molecular structures by various cells of the innate immune system, but also provide a functional association with subsequent mechanisms of adaptive immunity. TLR7 and TLR8 play a particularly important role in the innate immune response to RNA viruses due to their ability to recognise GU-rich single-stranded RNA molecules and subsequently activate intracellular signalling pathways resulting in expression of genes coding for various biological response modifiers (interferons, proinflammatory cytokines, chemokines). The aim of this review is to summarise the most recent knowledge on the role of TLRs in the innate immune response to HIV-1 and the role of TLR gene polymorphisms in the biology and in the clinical aspects of HIV infections. In addition, the role of TLR agonists as latency reversing agents in research to treat HIV infections and as immunomodulators in HIV vaccine research will be discussed.

Achyranthes bidentata Blume, a traditional Chinese medicine, is widely acknowledged for its function of invigorating the liver and kidneys and as a stranguria-relieving diuretic and used in the treatment of edema, gonorrhea, and other diseases. Polysaccharide (ABPS), isolated from Achyranthes bidentata Blume, has been demonstrated to have multiple biological activities including immunomodulatory effects. However, the mechanisms underlying the effects of ABPS have not been fully investigated. The present study is conducted to explore the underlying mechanism of immunomodulatory activities of ABPS. Results showed that ABPS significantly increased the secretion of IL-1β and TNF-α in J744 A.1 cells. Nitric oxide (NO) also significantly increased after ABPS treatment. The special antibodies (Toll-like receptor 4 (TLR4) antibody and CD14/TLR4 antibody) significantly decreased the activation, while the Toll-like receptor 2 (TLR2) antibody could not abolish this activation. Meanwhile, pyrrolidine dithiocarbamate (PDTC), a specific inhibitor of NF-κB, remarkably inhibited the secretion of IL-1β and TNF-α induced by ABPS in J744 A.1 cells. Western blotting (WB) and confocal laser scanning microscopy (CLSM) showed that ABPS promoted NF-κB translocation into the nucleus. Furthermore, the mRNA and protein expression of TLR4 and MyD88 were significantly increased after ABPS treatment. Taken together, these findings suggested that the immunomodulatory mechanism of ABPS was associated with the secretion of cytokines by stimulating the NF-κB pathway through TLR4/MyD88 signaling. [ABSTRACT FROM AUTHOR]

Achyranthes bidentata Blume, a traditional Chinese medicine, is widely acknowledged for its function of invigorating the liver and kidneys and as a stranguria-relieving diuretic and used in the treatment of edema, gonorrhea, and other diseases. Polysaccharide (ABPS), isolated from Achyranthes bidentata Blume, has been demonstrated to have multiple biological activities including immunomodulatory effects. However, the mechanisms underlying the effects of ABPS have not been fully investigated. The present study is conducted to explore the underlying mechanism of immunomodulatory activities of ABPS. Results showed that ABPS significantly increased the secretion of IL-1β and TNF-α in J744 A.1 cells. Nitric oxide (NO) also significantly increased after ABPS treatment. The special antibodies (Toll-like receptor 4 (TLR4) antibody and CD14/TLR4 antibody) significantly decreased the activation, while the Toll-like receptor 2 (TLR2) antibody could not abolish this activation. Meanwhile, pyrrolidine dithiocarbamate (PDTC), a specific inhibitor of NF-κB, remarkably inhibited the secretion of IL-1β and TNF-α induced by ABPS in J744 A.1 cells. Western blotting (WB) and confocal laser scanning microscopy (CLSM) showed that ABPS promoted NF-κB translocation into the nucleus. Furthermore, the mRNA and protein expression of TLR4 and MyD88 were significantly increased after ABPS treatment. Taken together, these findings suggested that the immunomodulatory mechanism of ABPS was associated with the secretion of cytokines by stimulating the NF-κB pathway through TLR4/MyD88 signaling.

In 2011, the Nobel Prize in Physiology or Medicine was awarded to three immunologists: Bruce A. Beutler, Jules A. Hoffmann, and Ralph M. Steinman. While Steinman was honored for his work on dendritic cells and adaptive immunity, Beutler and Hoffman received the prize for their contributions to discoveries in innate immunity. In 1996, Hoffmann found the toll gene to be crucial for mounting antimicrobial responses in fruit flies, first implicating this developmental gene in immune signaling. Two years later, Beutler built on this observation by describing a Toll-like gene, tlr4, as the receptor for the bacterial product LPS, representing a crucial step in innate immune activation and protection from bacterial infections in mammals. These publications spearheaded research in innate immune sensing and sparked a huge interest regarding innate defense mechanisms in the following years and decades. Today, Beutler and Hoffmann’s research has not only resulted in the discovery of the role of multiple TLRs in innate immunity but also in a much broader understanding of the molecular components of the innate immune system. In this review, we aim to collect the discoveries leading up to the publications of Beutler and Hoffmann, taking a close look at how early advances in both developmental biology and immunology converged into the research awarded with the Nobel Prize. We will also discuss how these discoveries influenced future research and highlight the importance they hold today.

Non-alcoholic steatohepatitis (NASH), also known as fatty liver disease (FLD), is a major public health problem. It is considered to be the hepatic manifestation of the metabolic syndrome. Chronic inflammation of the liver is an essential key in the progression from simple hepatic steatosis to steatohepatitis, the evolutionary stage of fatty liver disease. Moreover, the innate immune system plays a crucial role in the progression of hepatic inflammation. For this reason, it is of utmost importance to elucidate the connections between immune mechanisms, Toll-like receptor cytokine signalling, in order to find new effective treatments. Further studies are necessary to test theories presented in this paper. The elucidation of mechanisms underlying the progression of hepatic steatosis towards steatohepatitis is essential for the development of useful diagnosis and treatment for medical practice.

Despite advances in critical care medicine, infection remains a significant problem that continues to be complicated with the challenge of antibiotic resistance. Immunocompromised patients are highly susceptible to development of severe infection which often progresses to the life-threatening condition of sepsis. Thus, immunotherapies aimed at boosting host immune defenses are highly attractive strategies to ward off infection and protect patients. Recently there has been mounting evidence that activation of the innate immune system can confer long-term functional reprogramming whereby innate leukocytes mount more robust responses upon secondary exposure to a pathogen for more efficient clearance and host protection, termed trained immunity. Toll-like receptor (TLR) agonists are a class of agents which have been shown to trigger the phenomenon of trained immunity through metabolic reprogramming and epigenetic modifications which drive profound augmentation of antimicrobial functions. Immunomodulatory TLR agonists are also highly beneficial as vaccine adjuvants. This review provides an overview on TLR signaling and our current understanding of TLR agonists which show promise as immunotherapeutic agents for combating infection. A brief discussion on our current understanding of underlying mechanisms is also provided. Although an evolving field, TLR agonists hold strong therapeutic potential as immunomodulators and merit further investigation for clinical translation.

Inflammatory responses by the innate and adaptive immune systems protect against infections and are essential to health and survival. Many diseases including atherosclerosis, osteoarthritis, rheumatoid arthritis, psoriasis, and obesity involve persistent chronic inflammation. Currently available anti-inflammatory agents, including non-steroidal anti-inflammatory drugs, steroids, and biologics, are often unsafe for chronic use due to adverse effects. The development of effective non-toxic anti-inflammatory agents for chronic use remains an important research arena. We previously reported that oral administration of Oxy210, a semi-synthetic oxysterol, ameliorates non-alcoholic steatohepatitis (NASH) induced by a high-fat diet in APOE*3-Leiden.CETP humanized mouse model of NASH and inhibits expression of hepatic and circulating levels of inflammatory cytokines. Here, we show that Oxy210 also inhibits diet-induced white adipose tissue inflammation in APOE*3-Leiden.CETP mice, evidenced by the inhibition of adipose tissue expression of IL-6, MCP-1, and CD68 macrophage marker. Oxy210 and related analogs exhibit anti-inflammatory effects in macrophages treated with lipopolysaccharide in vitro, mediated through inhibition of toll-like receptor 4 (TLR4), TLR2, and AP-1 signaling, independent of cyclooxygenase enzymes or steroid receptors. The anti-inflammatory effects of Oxy210 are correlated with the inhibition of macrophage polarization. We propose that Oxy210 and its structural analogs may be attractive candidates for future therapeutic development for targeting inflammatory diseases.

Despite advances in critical care medicine, infection remains a significant problem that continues to be complicated with the challenge of antibiotic resistance. Immunocompromised patients are highly susceptible to development of severe infection which often progresses to the life-threatening condition of sepsis. Thus, immunotherapies aimed at boosting host immune defenses are highly attractive strategies to ward off infection and protect patients. Recently there has been mounting evidence that activation of the innate immune system can confer long-term functional reprogramming whereby innate leukocytes mount more robust responses upon secondary exposure to a pathogen for more efficient clearance and host protection, termed trained immunity. Toll-like receptor (TLR) agonists are a class of agents which have been shown to trigger the phenomenon of trained immunity through metabolic reprogramming and epigenetic modifications which drive profound augmentation of antimicrobial functions. Immunomodulatory TLR agonists are also highly beneficial as vaccine adjuvants. This review provides an overview on TLR signaling and our current understanding of TLR agonists which show promise as immunotherapeutic agents for combating infection. A brief discussion on our current understanding of underlying mechanisms is also provided. Although an evolving field, TLR agonists hold strong therapeutic potential as immunomodulators and merit further investigation for clinical translation. [ABSTRACT FROM AUTHOR]

Abstract Background Interactions of resident bacteria and/or their producing lipopolysaccharide (LPS) with sulcular epithelial keratinocytes may be regulated by autophagy in the gingival sulcus. In this study, we investigated an induction of bacterial autophagy in exfoliative sulcular keratinocytes of the gingival sulcus and cultured keratinocytes treated with Porphyromonas gingivalis-originated LPS (PgLPS). Results Exfoliative sulcular keratinocytes showed an induction of autophagy, in addition to increased expression of LPS-mediated factors including lipopolysaccharide-binding protein and toll-like receptors (TLRs), leading to co-localization of bacteria with autophagosomes. In contrast, exfoliative keratinocytes from the free gingiva did not show similar autophagy. Autophagy activity in human cultured keratinocyte cells (HaCaT) was induced by PgLPS, which was dependent partially on the AMP-activated protein kinase (AMPK) pathway via increased intracellular reactive oxygen species (ROS) and was in association with an activation of TLR4 signaling. After incubation of cultured keratinocytes with E.coli BioParticles following PgLPS stimulation, co-localization of bioparticles with autophagosomes was enhanced. Conversely, blockage of autophagy with 3-methyladenin and LPS-binding with polymyxin B led to significant reduction of co-localization of particles with autophagosomes. Conclusion These findings indicate that PgLPS-induced autophagy is at least partially responsible for interaction between bacteria and sulcular keratinocytes in the gingival sulcus.

The article gives a modern definition of functional disorders of the digestive organs, presents diagnostic criteria and a possible mechanism for their development in newborns and infants in accordance with the Roman criteria for revision IV (2016). Much of the information is devoted to the positive effects of probiotic strain Bifidobacterium animalis subsp. lactis (ВВ-12).

Summary: During human pregnancy, regulatory T cell (Treg) function is enhanced and immune activation is repressed allowing the growth and development of the feto–placental unit. Here, we have investigated whether human labour is associated with a reversal of the pregnancy‐induced changes in the maternal immune system. We tested the hypothesis that human labour is associated with a decline in Treg function, specifically their ability to modulate Toll‐like receptor (TLR)‐induced immune responses. We studied the changes in cell number, activation status and functional behaviour of peripheral blood, myometrial (myoMC) and cord blood mononuclear cells (CBMC) with the onset of labour. We found that Treg function declines and that Treg cellular targets change with labour onset. The changes in Treg function were associated with increased activation of myoMC, assessed by their expression of major histocompatibility complex (MHC) class II molecules and CBMC inflammatory cells. The innate immune system showed increased activation, as shown by altered monocyte and neutrophil cell phenotypes, possibly to be ready to respond to microbial invasion after birth or to contribute to tissue remodelling. Our results highlight changes in the function of the adaptive and innate immune systems that may have important roles in the onset of human labour. [ABSTRACT FROM AUTHOR]

Pattern recognition receptors (PRRs) coordinate the innate immune response and have a significant role in the development of multiple sclerosis (MS). Accumulating evidence has identified both pathogenic and protective functions of PRR signaling in MS and its animal model, experimental autoimmune encephalomyelitis (EAE). Additionally, evidence for PRR signaling in non-immune cells and PRR responses to host-derived endogenous ligands has also revealed new pathways controlling the development of CNS autoimmunity. Many PRRs remain uncharacterized in MS and EAE, and understanding the distinct triggers and functions of PRR signaling in CNS autoimmunity requires further investigation. In this brief review, we discuss the diverse pathogenic and protective functions of PRRs in MS and EAE, and highlight major avenues for future research.

Herpes simplex viruses type 1 (HSV-1) and type 2 (HSV-2) have co-evolved with humans for thousands of years and are present at a high prevalence in the population worldwide. HSV infections are responsible for several illnesses including skin and mucosal lesions, blindness and even life-threatening encephalitis in both, immunocompetent and immunocompromised individuals of all ages. Therefore, diseases caused by HSVs represent significant public health burdens. Similar to other herpesviruses, HSV-1 and HSV-2 produce lifelong infections in the host by establishing latency in neurons and sporadically reactivating from these cells, eliciting recurrences that are accompanied by viral shedding in both, symptomatic and asymptomatic individuals. The ability of HSVs to persist and recur in otherwise healthy individuals is likely given by the numerous virulence factors that these viruses have evolved to evade host antiviral responses. Here, we review and discuss molecular mechanisms used by HSVs to evade early innate antiviral responses, which are the first lines of defense against these viruses. A comprehensive understanding of how HSVs evade host early antiviral responses could contribute to the development of novel therapies and vaccines to counteract these viruses.

Pattern recognition receptors (PRRs) coordinate the innate immune response and have a significant role in the development of multiple sclerosis (MS). Accumulating evidence has identified both pathogenic and protective functions of PRR signaling in MS and its animal model, experimental autoimmune encephalomyelitis (EAE). Additionally, evidence for PRR signaling in non-immune cells and PRR responses to host-derived endogenous ligands has also revealed new pathways controlling the development of CNS autoimmunity. Many PRRs remain uncharacterized in MS and EAE, and understanding the distinct triggers and functions of PRR signaling in CNS autoimmunity requires further investigation. In this brief review, we discuss the diverse pathogenic and protective functions of PRRs in MS and EAE, and highlight major avenues for future research. [ABSTRACT FROM AUTHOR]

Toll-like receptors (TLRs) are associated with tumor growth and immunosuppression, as well as apoptosis and immune system activation. TLRs can activate apoptosis and innate and adaptive immunity pathways, which can be pharmacologically targeted for the development of anticancer oncotherapies. Several studies and clinical trials indicate that TLR agonists are promising adjuvants or elements of novel therapies, particularly when used in conjunction with chemotherapy or radiotherapy. An increasing number of studies suggest that the activation of TLRs in various cancer types is related to oncotherapy; however, before this finding can be applied to clinical practice, additional studies are required. Research suggests that TLR agonists may have potential applications in cancer therapy; nevertheless, because TLR signaling can also promote tumorigenesis, a critical and comprehensive evaluation of TLR action is warranted. This review focuses on recent studies that have assessed the strengths and weaknesses of utilizing TLR agonists as potential anticancer agents. [ABSTRACT FROM AUTHOR]