Anti-viral role of toll like receptor 4 in hepatitis B virus infection: An in vitro study

AIM Toll like receptors plays a significant anti-viral role in different infections. The aim of this study was to look into the role of toll like receptor 4(TLR4) in hepatitis B virus(HBV) infection.METHODS Real time PCR was used to analyze the transcription of TLR4 signaling molecules, cell cycle regulators and HBV DNA viral load after triggering the Hep G2.2.15 cells with TLR4 specific ligand. Nuclear factor(NF)-κB translocation on TLR4 activation was analyzed using microscopic techniques. Protein and cell cycle analysis was done using Western Blot and FACS respectively.RESULTS The present study shows that TLR4 activation represses HBV infection. As a result of HBV suppression, there are several changes in host factors which include partial release in G1/S cell cycle arrest and changes in host epigenetic marks. Finally, it was observed that anti-viral action of TLR4 takes place through the NF-κB pathway.CONCLUSION The study shows that TLR4 activation in HBV infection brings about changes in hepatocyte microenvironment and can be used for developing a promising therapeutic target in future.

Relationship of Toll-Like Receptors 2 and 4 Gene Polymorphisms with Essential Hypertension in Chinese Han Population

Objective: There are numerous studies suggesting that genetic polymor-phisms of inflammation factors Toll-like receptors 2 and 4 (TLR2, TLR4) might play a role in the pathophysiological process of hypertension. In this study, we evaluated the association in a sample of members of the Chinese Han population. Method: We selected four single nucleotide polymor-phisms (SNP) of TLR2 (rs3804099, rs3804100, rs7656411) and TLR4 (rs1927906) genes, and measured the distributions of genotypic and allelic frequencies in 1063 participants, including 391 essential hypertension pa-tients and 672 controls. Result: No significant differences in the genotypic and allelic frequencies of the four SNPs were detected between cases and controls. However, three haplotypes, CCG, TTG and TTT of TLR2, were significantly associated with a decrease in the risk of essential hyperten-sion (OR: 0.512, 95% CI: 0.397 - 0.660, P P = 0.0038;OR: 0.797, 95% CI: 0.667 - 0.952, P = 0.0122, respectively). Inversely, the risk of essential hypertension increased sig-nificantly in patients with the CTG, TCG or TCT haplotypes (OR: 2.924, 95% CI: 2.157 - 3.963, P P P Conclusion: Our study suggested that haplotypes (CCG, TTG, TTT, CTG, TCG and TCT) of TLR2 might have profound effects on the development of essential hypertension in the Chinese Han population.

广谱模式识别分子Toll-like receptor 2的研究进展

TLR-2（Toll-like receptor 2,TLR-2）是哺乳动物TLRs（Toll-like receptors,TLRs）家族的一员,作为细胞表面的天然受体蛋白,主要参与病原微生物产物的识别及炎症信号传导,介导天然抗感染兔疫;最近又发现其参与机体对非感染因子所致炎性组织损伤的识别。通过对TLR-2参与的识别和细胞内信号传导机制的研究,可为深入探讨抵御微生物感染的机制、对自身正常与非正常组织的识别提供新的思路。

人Toll-like receptor 2配基模拟肽的初步研究

TLR-2(Toll-likereceptor2)是介导天然免疫的重要模式识别分子,可参与识别多种病原体及其产物.为探索被TLR-2所识别配基的结构共性,以真核细胞表达的人TLR-2胞外段蛋白(A26￣T588)为钓饵筛选噬菌体12肽库,获得一高度保守的阳性噬菌体克隆P12-1,实验发现P12-1可与不同形式的TLR-2胞外段结合,并且可刺激细胞分泌TNFα,提示P12-1可能模拟TLR-2配基的结构与生物学活性.

Toll-like receptor 4-mediated signaling participates in apoptosis of hippocampal neurons

The phosphatidylinositol 3 kinase （PI3K）/protein kinase B （AKT） signaling pathway is considered important for cell survival and has been shown to mediate various anti-apoptotic biological effects. This study explored the role of the Toll-like receptor 4 （TLR4）-mediated PI3K/AKT-glycogen syn-thase kinase 3β （GSK-3β） signaling pathways in lipopolysaccharide-induced apoptosis in a primary culture of hippocampal neurons. Results demonstrated that the apoptotic ratio of hippocampal neurons stimulated by lipopolysaccharide was significantly higher compared with the control group. Both the expression of P-AKTser473 and P-GSK-3βSserg in hippocampal neurons stimulated by lipopolysaccharide decreased compared with the control, while the level of active Caspase-3 and the ratio of Bax/Bcl-2 were significantly increased. The level of active Caspase-3 and the ratio of Bax/Bcl-2 in hippocampal neurons treated with TLR4 antibody or the GSK-3β inhibitor, LiCl, de-creased before intervention with lipopolysaccharide, but increased after treatment with the AKT in-hibitor, LY294002. These findings suggest that the TLR4-PI3K/AKT-GSKβ signaling pathway may be involved in lipopolysaccharide-induced apoptosis of hippocampal neurons.

Upregulated functional expression of Toll like receptor 4 in mesenchymal stem cells induced by lipopolysaccharide

Background The coordinated change of haematopoietic supporting microenvironment in bone marrow （BM） is crucial for innate immunity and inflammation. As the precursors of marrow stroma, BM derived mesenchymal stem cells （MSCs） promote haematopoietic function, but their roles in innate immunity or inflammation have not been investigated. Here we investigated the expression of Toll like receptor 4 （TLR-4） and the effect of lipopolysaccharide （LPS） on its expression in BM MSCs in vitro. Methods MSCs were harvested from adult rat＇s BM cells by density gradient centrifugation and adhesive culture. The purity of MSCs were identified with the cell morphological feature and osteogenic capacity, the phenotypes were tested by flow cytometry. Cultured MSCs were treated by LPS （1 μg/ml, 10μg/ml or 100μg/ml） for 24 hours. The relative expression levels of TLR-4 mRNA were detected by semiquantitative reverse transcription polymerase chain reaction and costimulatory molecules （CD80, CD86 and MHC-Ⅱ） expressed on MSCs were analyzed by flow cytometry. The levels of tumor necrosis factor-α （TNF-α） in supernatants were determined by enzyme linked immunosorbent assay. Results After incubation with LPS, MSCs expressed the higher levels of TLR-4 mRNA, costimulatory molecules and TNF-α than the untreated group： LPS 10 μg/ml was the most effective （P〈0.01）; the levels of TLR-4 mRNA, costimulatory molecules and TNF-α decreased when MSCs were exposed to 100 μg/ml LPS. Except for MHC-Ⅱ and TNF-α （P〉0.05）, the levels of CD80, CD86 and TLR-4 mRNA were significantly lower than that in the treated group of 10 μg/ml （P〈0.01）. Conclusion MSCs expressed TLR-4 mRNA. LPS activated the functional expression levels of TLR-4 in MSCs although the activity may depend on the concentration of LPS.

Expression and Immune Effect of Toll-Like Receptor 4 in Human Trophoblast Cells

This study investigated the expression and immune effect of TLR4 in human trophoblast cells. The expression level of TLR4 mRNA in normal and LPS-stimulated human term trophoblast cells （1 mg/L LPS, 12 h） was detected by RT-PCR. In LPS-stimulated human term trophoblast cells of TLR4-blocked group and non-TLR4-blocked group, and normal term trophoblast cells of blank control group, apoptosis rate was measured by flow cytometry （FCM）, and the level of TNF-α determined by using enzyme linked immunosorbent assay （ELISA） respectively. RT-PCR results showed that the expression level of TLR4 mRNA in LPS-stimulated human trophoblast cells was significantly higher than that in normal cells （P〈0.01）. FCM revealed that there was significant difference in apoptosis rate of LPS-stimulated human term trophoblast cells between TLR4-blocked group and non-TLR4-blocked group （P〈0.05）, or between TLR4 antibody-blocked group and blank control group. ELISA indicated that the level of TNF-α in LPS-stimulated human trophoblast cells also had statistical differences between TLR4 antibody-blocked group and non-TLR4 antibody-blocked group （P〈0.05）. Our results suggest that TLR4 plays an important role in the immunological mechanism of apoptosis and secretion of TNF-α of human term trophoblast cells stimulated by LPS.

Toll like receptors and inflammatory factors in sepsis and differential expression related to age

In recent years, the incidence of systematic severe .infection in intensive care units （ICUs） has increased significantly. Sepsis is a＂ complex, multifactorial syndrome that can develop into conditions of different severity, described as severe sepsis or septic shock. The immunology of severe sepsis and septic shock is poorly defined, despite many studies investigating the pathogenesis of this syndrome. With mortality rates of up to 50%, greater understanding of the interactions between host and microbe is necessary to improve patient outcome. Given the rapid progression of sepsis and immediate recruitment of the inflammatory cytokine cascade, the early innate response of the immune system to the pathogen is likely to play a critical role.

Toll-like receptor激动剂耐受分子机制和疟原虫慢性感染

小剂量LPS预刺激可引起内毒素耐受,能提高小鼠在致死剂量LPS再次刺激后的存活率,其机制可能与铎样受体TLR(Toll-like receptor)4信号通路的下调有关。近年来的研究发现,其他TLR激动剂同样可以引起宿主对相应TLR激动剂和LPS的耐受,后者称为交叉耐受(cross tolerance),而且疟原虫慢性感染同样能诱导类似TLR激动剂耐受的现象,因此,研究TLR激动剂耐受分子机制有助于脓毒血症预防和对慢性感染机制的理解。

Toll样受体对成骨及破骨细胞功能的调节

背景:Toll样受体是一类重要的模式识别受体,通过识别特定的分子模式在病原体免疫、细胞因子合成等方面具有重要功能。既往的研究发现,不同种类的骨组织细胞同样表达Toll样受体。激活或抑制Toll样受体可通过多种途径对成骨与破骨细胞功能造成显著影响。目的:总结Toll样受体在成骨及破骨细胞中的表达及作用途径,以进一步阐明生理及病理状态下Toll样受体参与调控的生物学机制。方法:检索截至2022年12月的PubMed、中国知网等文献数据库中的相关文献,中文检索词为“Toll样受体,成骨细胞,破骨细胞,间充质干细胞,巨噬细胞,细胞因子,信号通路”,英文检索词为“toll-like receptor,osteoblast,osteoclast,mesenchymal stem cells,macrophage,cytokine,signaling pathway”,并根据研究需要确立相应的标准,对最终所得文献进行筛选。结果与结论:①Toll样受体可通过激活相关信号通路直接调节成骨、破骨细胞分化;②Toll样受体的激活诱导细胞因子的产生,发挥调节效应;③Toll样受体的激活能够对成骨、破骨细胞的生存及迁移能力产生影响;④在某些疾病及病理环境中,成骨及破骨细胞中的Toll样受体被激活,参与细胞间的相互作用。

桑白皮提取物抑制高迁移率族蛋白/Toll样受体4通路对肺炎支原体肺炎大鼠的保护机制

目的:探究桑白皮提取物对肺炎支原体(MP)肺炎大鼠的药效,以及对高迁移率族蛋白(HMGB-1)/Toll样受体4(TLR4)信号通路的影响。方法:将Wistar雄性大鼠随机分为对照组、MP肺炎模型组、阿奇霉素(阳性对照)组及桑白皮提取物低、中、高剂量组[2、4、8 g/(kg·d)],每组各12只。除对照组外,其余大鼠构建MP肺炎大鼠模型,并给予相应剂量的药物处理。显微镜下计数肺泡灌洗液(BALF)中炎性细胞计数;采用酶联免疫吸附试验(ELISA)法检测血清中炎性细胞因子水平;苏木精-伊红(HE)染色观察肺组织病理变化;Western blotting法和免疫组化检测肺组织HMGB-1、TLR4、p-NF-κB p65蛋白表达水平。结果:对照组大鼠肺组织细胞排列正常,无病变;MP肺炎模型组大鼠肺组织异常,大量炎性细胞浸润;经桑白皮提取物给药后,大鼠肺组织损伤明显减轻,炎性细胞浸润明显减少。与对照组相比,MP肺炎模型组大鼠肺系数、BALF中炎性细胞计数、血清中白细胞介素(IL)-6、肿瘤坏死因子(TNF)-α水平及肺组织中HMGB-1、TLR4、p-NF-κB p65蛋白水平升高,IL-10水平降低(P<0.05)。与模型组相比,桑白皮提取物各剂量组和阿奇霉素组大鼠上述指标趋势相反(P<0.05)。结论:桑白皮提取物可能通过抑制HMGB-1/TLR4信号通路,减轻炎症反应,发挥对MP肺炎大鼠的保护作用。

巨型艾美耳球虫感染对鸡Toll样受体的影响

为了探究巨型艾美耳球虫(Eimeria maxima)感染对宿主局部免疫组织盲肠扁桃体和系统免疫组织(脾脏和外周血)中Toll样受体(Toll like receptor,TLR)的影响,用巨型艾美耳球虫感染雏鸡,感染后第0、3、7和11天,采集鸡盲肠扁桃体、外周血和脾脏淋巴细胞,用实时荧光定量PCR检测上述组织中8种鸡TLR的mRNA水平变化。结果显示:TLR4和TLR21 mRNA水平在3种组织中无显著变化;TLR2 mRNA水平在感染后第3天开始在外周血和脾脏中显著下降(P<0.05),在盲肠扁桃体中第3和7天无显著变化,在第11天显著上升(P<0.01)。TLR1、TLR3、TLR5、TLR7和TLR15 mRNA水平在3种组织中显著上升(P<0.05),但应答时间有所差异,具体为TLR1和TLR3 mRNA水平在盲肠扁桃体中在第3天开始上升,而在外周血和脾脏中第7天开始上升;TLR5和TLR15 mRNA水平在外周血和脾脏中第3天开始上升,而在盲肠扁桃体中第7天开始上升。结果表明:巨型艾美耳球虫感染上调宿主3种组织中的TLR1、TLR3、TLR5、TLR7和TLR15 mRNA水平,下调外周血和脾脏中的TLR2 mRNA水平;盲肠扁桃体TLR1和TLR3 mRNA水平上升早于外周血和脾脏,而其TLR5和TLR15 mRNA水平上升晚于外周血和脾脏。本研究为揭示鸡TLR在抗球虫感染中的作用提供依据,也为揭示鸡球虫先天性免疫机制提供参考。

Toll样受体4信号通路在心力衰竭中的应用价值

心力衰竭是全球发病率最高的疾病之一,在心力衰竭及其合并症的发生和发展过程中炎症机制起着至关重要的作用。大量研究表明Toll样受体4信号通路可通过介导不同的炎症因子,对心肌造成损害。因此近期发现Toll样受体4信号通路可用于预测心力衰竭及其合并症病情的严重程度及预后,同时也可作为许多新型抗心力衰竭药物的靶点,改善症状,使心力衰竭患者获益。现就Toll样受体4信号通路在心力衰竭中上述两方面的应用价值做一综述。

Expressions of Toll-like receptors 3,4,7,and 9 in cervical lesions and their correlation with HPV16 infection in Uighur women

Recent findings show that Toll-like receptors(TLRs) expressed in immune cells play a crucial role in the innate immune response and the subsequent induction of adaptive immune responses against microbial infection on tissue injury.Furthermore,expression of TLRs in cancer cells is associated with tumor proliferation and invasion.To explore the role of TLRs expression in cervical carcinogenesis in Uighur women,we detected the expressions of TLR3,TLR4,TLR7,and TLR9 in 25 normal cervical tissues,64 cervical intraepithelial neoplasia(CIN) tissues,and 63 cervical squamous cell carcinoma(CSCC) tissues using immunohistochemical staining,as well as human papillomavirus type 16(HPV16) infection using PCR.All samples used in this study were from Xinjiang Uighur women.We found the expression levels of TLR4,TLR7,and TLR9 were significantly higher in CIN and CSCC than in normal controls(P < 0.05).Up-regulation of TLR4 and TLR7 were correlated with tumor differentiation but not FIGO stage or lymph node metastasis(P > 0.05).Up-regulation of TLR9 was correlated with lymph node metastasis(P < 0.05) but not tumor differentiation or FIGO stage(P > 0.05).We also analyzed the correlation between the expressions of TLRs and HPV16 infection and found that the expressions of TLR4 and TLR9 significantly correlated with HPV16 infection in CIN(r = 7.434,P = 0.006;r = 7.123,P = 0.008) and CSCC(r = 6.423,P = 0.001;r = 8.478,P = 0.004),whereas the expression of TLR3 was not significantly different in any of the three groups and had no significant correlation with HPV16 infection.Our results suggest that high expression of TLR4,TLR7,and TLR9 may play important roles in the development and progression of CIN and CSCC in Uighur women,and the expressions of TLR4 and TLR9 can be up-regulated by HPV16 infection.

Role of gut microbiota and Toll-like receptors in nonalcoholic fatty liver disease

Emerging data have shown a close association between compositional changes in gut microbiota and the development of nonalcoholic fatty liver disease(NAFLD).The change in gut microbiota may alter nutritional absorption and storage.In addition,gut microbiota are a source of Toll-like receptor(TLR)ligands,and their compositional change can also increase the amount of TLR ligands delivered to the liver.TLR ligands can stimulate liver cells to produce proinflammatory cytokines.Therefore,the gut-liver axis has attracted much interest,particularly regarding the pathogenesis of NAFLD.The abundance of the major gut microbiota,including Firmicutes and Bacteroidetes,has been considered a potential underlying mechanism of obesity and NAFLD,but the role of these microbiota in NAFLD remains unknown.Several reports have demonstrated that certain gut microbiota are associated with the development of obesity and NAFLD.For instance,a decrease in Akkermansia muciniphila causes a thinner intestinal mucus layer and promotes gut permeability,which allows the leakage of bacterial components.Interventions to increase Akkermansia muciniphila improve the metabolic parameters in obesity and NAFLD.In children,the levels of Escherichia were significantly increased in nonalcoholic steatohepatitis(NASH)compared with those in obese control.Escherichia can produce ethanol,which promotes gut permeability.Thus,normalization of gut microbiota using probiotics or prebiotics is a promising treatment option for NAFLD.In addition,TLR signaling in the liver is activated,and its downstream molecules,such as proinflammatory cytokines,are increased in NAFLD.To data,TLR2,TLR4,TLR5,and TLR9 have been shown to be associated with the pathogenesis of NAFLD.Therefore,gut microbiota and TLRs are targets for NAFLD treatment.

Toll样受体在冠心病中的研究进展及靶向药物分析

冠心病(CHD)是一种以慢性炎症刺激和斑块聚集为特征的心血管疾病(CVD),严重威胁着成千上万患者的生命安全。研究发现Toll样受体(TLRs)通过介导免疫激活参与多种炎性因子的产生,进而在CHD的发生发展中发挥着复杂的双向调节作用。靶向TLRs的治疗具有抗动脉粥样硬化的潜在作用。本文就TLRs信号在CHD中的作用机制及TLRs相关抗动脉粥样硬化药物的最新研究进展做一综述。

Controversial role of toll-like receptors in acute pancreatitis

Acute pancreatitis(AP)is a common clinical condition with an incidence of about 300 or more patients per million annually.About 10%-15%of patients will develop severe acute pancreatitis(SAP)and of those, 10%-30%may die due to SAP-associated complications.Despite the improvements done in the diagnosis and management of AP,the mortality rate has not significantly declined during the last decades.Toll-like receptors(TLRs)are pattern-recognition receptors that seem to play a major role in the development of numerous diseases,which make these molecules attractive as potential therapeutic targets.TLRs are involved in the development of the systemic inflammatory response syndrome,a potentially lethal complication in SAP.In the present review,we explore the current knowledge about the role of different TLRs that have been described associated with AP.The main candidate for targeting seems to be TLR4,which recognizes numerous damage-associated molecular patterns related to AP.TLR2 has also been linked with AP,but there are only limited studies that exclusively studied its role in AP.There is also data suggesting that TLR9 may play a role in AP.

Control of hepatitis B virus replication by interferons and Toll-like receptor signaling pathways

Hepatitis B virus(HBV) infection is one of the major causes of liver diseases, affecting more than 350 million people worldwide. The interferon(IFN)-mediated innate immune responses could restrict HBV replication at the different steps of viral life cycle. Indeed, IFN-α has been successfully used for treatment of patients with chronic hepatitis B. However, the role of the innate immune response in HBV replication and the mechanism of the anti-HBV effect of IFN-α are not completely explored. In this review, we summarized the currently available knowledge about the IFN-mediated anti-HBV effect in the HBV life cycle and the possible effectors downstream the IFN signaling pathway. The antiviral effect of Toll-like receptors(TLRs) in HBV replication is briefly discussed. The strategies exploited by HBV to evade the IFN- and TLR-mediated antiviral actions are summarized.

Betaine inhibits Toll-like receptor 4 expression in rats with ethanol-induced liver injury

AIM:To test whether ethanol feeding could induce Toll-like receptor 4(TLR4)responses,assess the hepatoprotective effect of betaine and its inhibitive effect on TLR4 in animal models of alcoholic liver injury.METHODS:Forty-eight female Sprague-Dawley rats were randomly divided into four groups as control,model,low and high dose betaine groups.Except control group,all rats were fed with high fat-containing diet plus ethanol and fish oil gavages for 8 wk.Betaine was administered intragastrically after exposure of ethanol for 4 wk.The changes of liver histology were examined.The expression of TLR4 mRNA and protein was detected by RT-PCR and Western blotting,respectively.The serum aminotransferase activity alanine transarninase(ALT),aspartate aminotransferase(AST),serum endotoxin,and liver inflammatory factors tumor necrosis factor-α(TNF-α),interferon-γ(IFN-γ),interleukin-18(IL-18)were also assayed.RESULTS:Compared with control group,rats of model group developed marked liver injury,accompanied by an increase of ALT(159.41±7.74 U/L vs 59.47± 2.34 U/L,P<0.0001),AST(248.25±1.40 U/L vs 116.89±3.48 U/L,P<0.0001),endotoxin(135.37± 30.17 ng/L vs 44.15±7.54 ng/L,P<0.0001),TNF-α(20.81±8.58 pg/mL vs 9.34±2.57 pg/mL,P=0.0003),IFN-γ(30.18±7.60 pg/mL vs 16.86±9.49 pg/mL,P= 0.0039)and IL-18(40.99±8.25 pg/mL vs 19.73±9.31 pg/mL,P=0.0001).At the same time,the expression of TLR4 mRNA and protein was markedly induced in the liver after chronic ethanol consumption(1.45±0.07 vs 0.44±0.04,P<0.0001;1.83±0.13 vs 0.56±0.08,P<0.0001).Compared with model group,betaine feeding resulted in significant decreases of ALT(64.93 ±6.06 U/L vs 159.41±7.74 U/L,P<0.0001),AST(188.73±1.11 U/L vs 248.25±1.40 U/L,P<0.0001),endotoxin(61.80±12.56 ng/L vs 135.37±30.17 ng/L,P<0.0001),TNF-α(9.79±1.32 pg/mL vs 20.81± 8.58 pg/mL,P=0.0003),IFN-γ(18.02±5.96 pg/mL vs 30.18±7.60 pg/mL,P=0.0008)and IL-18(18.23±7.01 pg/mL vs 40.99±8.25 pg/mL,P<0.0001).Betaine also improved liver steatosis.The expression levels of TLR4 mRNA or protein in liver tissues were significantly lowered(0.62±0.04 vs 1.45±0.07,P<0.0001;and 0.65±0.06 vs 1.83±0.13,P<0.0001).There was a statistical difference of TLR4 mRNA and protein expression between high-and low-dose betaine groups(0.62±0.04 vs 0.73±0.05,P<0.0001,and 0.65±0.06 vs 0.81±0.09,P<0.0001).CONCLUSION:Betaine can prevent the alcoholinduced liver injury effectively and improve the liver function.The expression of TLR4 increases significantly in ethanol-fed rats and betaine administration can inhibit TLR4 expression.

Toll-like receptor signaling in colorectal cancer:carcinogenesis to cancer therapy

Toll-like receptors(TLRs)are germ line encoded innate immune sensors that recognize conserved microbial structures and host alarmins,and signal expression of major histocompatibility complex proteins,costimulatory molecules,and inflammatory mediators by macrophages,neutrophils,dendritic cells,and other cell types.These protein receptors are characterized by their ability to respond to invading pathogens promptlyby recognizing particular TLR ligands,including flagellin and lipopolysaccharide of bacteria,nucleic acids derived from viruses,and zymosan of fungi.There are2 major TLR pathways;one is mediated by myeloid differentiation factor 88(MYD88)adaptor proteins,and the other is independent of MYD88.The MYD88-dependent pathway involves early-phase activation of nuclear factor of kappa light polypeptide gene enhancer in B-cells 1(NF-κB1)and all the TLRs,except TLR3,have been shown to activate this pathway.TLR3and TLR4 act via MYD88-independent pathways with delayed activation of NF-κB signaling.TLRs play a vital role in activating immune responses.TLRs have been shown to mediate inflammatory responses and maintain epithelial barrier homeostasis,and are highly likely to be involved in the activation of a number of pathways following cancer therapy.Colorectal cancer(CRC)is one of the most common cancers,and accounts for almost half a million deaths annually worldwide.Inflammation is considered a risk factor for many common malignancies including cancers of the colorectum.The key molecules involved in inflammation-driven carcinogenesis include TLRs.As sensors of cell death and tissue remodeling,TLRs may have a universal role in cancer;stimulation of TLRs to activate the innate immune system has been a legitimate therapeutic strategy for some years.TLRs 3/4/7/8/9 are all validated targets for cancer therapy,and a number of companies are developing agonists and vaccine adjuvants.On the other hand,antagonists may favor inhibition of signaling responsible for autoimmune responses.In this paper,we review TLR signaling in CRC from carcinogenesis to cancer therapy.