The innate immune system in the intestine

The innate immune system provides the first line of host defense against invading pathogens. Innate immune responses are initiated by germline-encoded PRR, which recognize specific structures expressed by microorganisms. TLR are a family of PRR which sense a wide range of microorganisms, including bacteria, fungi, protozoa and viruses. TLR are also expressed in the intestine and are critical for intestinal homeostasis. Recently, cytoplasmic PRR, such as NLR and RLR, have been shown to detect pathogens that have invaded the cytosol. One of the NLR, NOD2, is thought to be involved in the pathogenesis of Crohn's disease. This review focuses on the innate immune responses triggered by PRR in the intestine.     

大鼠白念珠菌支气管肺感染时肺组织Toll样受体2的表达及意义

目的 探讨Toll样受体2(TLR2)在白念珠菌支气管肺感染大鼠肺组织模型中的表达及意义.方法 建立白念珠菌支气管肺感染大鼠模型,观察感染后肺组织病理形态学改变,采用免疫组织化学法观察感染后不同时间(第3天、第7天)白念珠菌支气管肺感染大鼠肺组织TLR2的表达,并与未感染组进行比较.结果 大鼠白念珠菌支气管肺感染后肺组织TLR2表达水平明显升高.结论 白念珠菌支气管肺感染肺组织TLR2表达增高可能参与感染的炎症反应.     

Toll样受体4对动脉粥样硬化发生、发展的研究进展

动脉粥样硬化（atherosclerosis,AS）是多种细胞、炎性介质参与形成的慢性炎症性疾病。Toll样受体家族（Toll like receptors,TLRs）中的TLR4是机体重要的诱导分泌多种炎性因子的模式识别受体。现有证据表明,TLR4不仅产生多种炎性因子诱发血管炎症反应,而且促进AS斑块形成和发展,造成斑块不稳定,甚至破裂,对AS的发生、发展具有重要作用。因此,了解TLR4对AS的影响有助于发现新的治疗靶点和对策。主要对TLR4在AS发病机制和易损斑块发展中的作用进行综述。     

Cytokine responses to eye spray adjuvants for enhancing vaccine‐induced immunity in chickens

Eye spray influenza vaccines for chickens are increasingly available; however, how to enhance cellular and antibody responses to them remains undetermined. Here, eye‐drops containing the immune‐enhancing adjuvants Pam2CSK4 or polyI:C were assessed in chickens. Application of these TLR agonists to chicken conjunctiva resulted in up‐regulation of IL‐1β, but not other cytokines, including IFN and IL‐6, in the spleen, lung and Harderian gland. Thus, responses to adjuvant applied to the conjunctival mucosa of chickens differ from those expected from the responses to intra‐nasal adjuvants in mammals. Identifying an appropriate delivery route for adjuvants is crucial for evoking immune responses in chickens.     

TLR4信号转导通路在肿瘤中的作用

慢性炎症与恶性肿瘤密切相关,Toll样受体4（TLR4）在肿瘤中的广泛表达提示其在慢性炎症致瘤机制中发挥重要作用。活化肿瘤细胞TLR4不仅促进肿瘤的生成和转移,而且参与肿瘤的免疫逃逸。另一方面,免疫佐剂又通过激活免疫细胞的TLR4信号产生抗肿瘤免疫。因此,TLR4在肿瘤中起着双刃剑的作用。     

肺炎克雷伯菌生物膜对小鼠腹腔巨噬细胞TLRs受体表达的影响

目的研究肺炎克雷伯菌生物膜对小鼠腹腔巨噬细胞TEas受体表达的影响,探索机体抗生物膜（biofdm,BF）感染免疫的特点。方法将雄性昆明种小鼠40只随机分成2组,一组腹腔植入体外形成肺炎克雷伯菌生物膜的硅胶片,建立留置性医疗装置BF感染模型实验组,另一组植入与实验组同等量的浮游菌作为对照组。实时定量PCR分析2组巨噬细胞TLRsmRNA的表达水平,流式细胞仪检测分析蛋白的表达水平。结果实验生物膜组巨噬细胞TLR2、TLR4mRNA相对表达量是对照浮游菌组的0．23和0．24倍：实验组TLR2、TLR4蛋白表达率分别是（23．27±2．73）％和（15．83±2．04）％,明显低于对照组的（33．42±3．72）％、（21．75±1．25）％（P〈0．05）。结论与浮游菌相比,BF能下调小鼠腹腔巨噬细胞TLR2、TLR4表达,从而影响机体的免疫功能,这可能是BF相对浮游菌更容易逃脱机体免疫防御系统、引起慢性感染的机制之一。     

Transcriptional modulation of pattern recognition receptors in chronic colitis in mice is accompanied with Th1 and Th17 response

Pattern recognition receptors (PRRs) may contribute to inflammatory bowel diseases (IBD) development due to their microbial-sensing ability and the unique microenvironment in the inflamed gut. In this study, the PRR mRNA expression profile together with T cell-associated factors in the colon was examined using a chronic colitis mice model. 8–12 week old C57BL/6 mice were exposed to multiple dextran sodium sulfate (DSS) treatments interspersed with a rest period to mimic the course of chronic colitis. The clinical features and histological data were collected. The mRNA expressions of colonic PRRs, T cell-associated components were measured. Finally, the colons were scored for Foxp3+ cells. During chronic colitis, the histological data, but not the clinical manifestations demonstrated characteristic inflammatory symptoms in the distal colon. In contrast to acute colitis, the expression of all Toll-like receptors (Tlrs), except Tlr5 and Tlr9, was unaffected after repeated DSS treatments. The expression of Nod1 was decreased, while Nod2 increased. After third DSS treatment, only the expressions of Tlr3 and Tlr4 were significantly enhanced. Unlike other PRRs, decreased Tlr5 and increased Tlr9 mRNA expression persisted during the chronic colitis period. As the colitis progress, only the mRNA expression of Ifnγ and Il17 staid increased during chronic colitis, while the acute colitis-associated increase of Il23, and Il10 and Il12 was abolished. Finally, increased histological score of Foxp3+ cell in colon was found during the chronic colitis period. This study provides an expression pattern of PRRs during chronic colitis that is accompanied by a Th1- and Th17 cell-mediated immune response.     

Lipopolysaccharide regulates toll-like receptor 4 expression in human aortic smooth muscle cells

Lipopolysaccharide (LPS) is a potent activator of cells of the immune and inflammatory systems, including macrophages, monocytes, and endothelial cells (EC). Toll-like receptor 4 (TLR4) has been identified as the primary receptor for LPS. Vascular smooth muscle cells (VSMCs) likely contribute significantly to the inflammation induced by low-level LPS in patients who are at risk for atherosclerosis. Previous study indicated that functional TLR4 was present in VSMCs. However, it remains unclear whether low levels of commercial LPS preparations can affect TLR4 expression in early stage. Here Real-time quantitative PCR analysis was used to detect TLR4 mRNA expression; Immunofluorescence, Western blot analysis and flow cytometry were used to examine TLR4 protein expression. It was shown that TLR4 was present in Human Aortic Smooth Muscle Cells (HASMCs). LPS can up-regulate TLR4 mRNA and protein expression in HASMCs in dose- and time-dependent manner. These data indicate that LPS regulate TLR4 expression in HASMCs.     

TOLL样受体4在哮喘大鼠气道平滑肌细胞增殖、凋亡中的作用

目的:探讨Toll样受体4(TLR4)在哮喘状态下气道平滑肌细胞(ASMCs)增殖、凋亡中的作用.方法:建立哮喘大鼠模型,分离、培养哮喘大鼠气道平滑肌细胞,应用小分子RNA干扰技术、脂质体转染法进行小分子RNA-TLR4的转染、MTT,法检测细胞增殖、TUNNEL法检测细胞凋亡情况、逆转录聚合酶链式反应(RT-PCR)...     

膀胱癌中唾液酸酶Neu1的异常表达对Toll样受体的影响

哺乳动物细胞内的某些蛋白质或脂类可以被糖基化修饰,而糖链末端往往存在唾液酸化的现象,催化添加唾液酸的酶为糖基转移酶(sialyltransferase,ST),而去除唾液酸的为唾液酸酶(sialidase,SA或称为neuraminidase,NEU).本实验检测了人膀胱正常上皮细胞HCV29、非浸润性膀胱癌细胞KK47和浸润性膀胱癌细胞YTS-1中唾液酸的表达,发现恶性肿瘤细胞中唾液酸的含量高于正常细胞;进一步分析唾液酸酶和唾液酸转移酶的表达,发现唾液酸酶Neu1在正常细胞中表达最高,在良性肿瘤细胞中次之,在恶性肿瘤细胞中表达最低,推测在膀胱癌中Neu1对唾液酸的异常表达起着主要作用.同时,膀胱癌细胞中Toll样受体1,2,3,4(toll-like receptors,TLRs)表达趋势也与Neu1一致.利用TGF-β处理HCV29,使之发生上皮间质转化(epithelial-mesenchymal transition,EMT),细胞中Neu1和TLR3表达明显减少;将Neu1基因沉默后,TLR3表达也明显减少.此外,在YTS-1细胞中过表达Neu1,TLR3表达增高且激活了下游NF-κB通路.这一结果说明膀胱癌中Neu1与TLR3的表达有着密切的关系,这为膀胱癌的分子机理研究提供了工作基础.     

Characterization of mesenchymal stem cells under the stimulation of Toll‐like receptor agonists

Infective factors cause the perpetuation of inflammation as a result of the permanent exposure of the immune system to exogenous or endogenous products of virus or bacteria. Mesenchymal stem cells (MSCs) can be exposed to this infective environment, which may change the characteristics and therapeutic potency of these MSCs. MSCs have the ability to repair damaged and inflamed tissues and regulate immune responses. In this study, we demonstrated that MSCs express functional Toll‐like receptors (TLR) 3 and 4, the Toll‐like receptor families that recognize the signals of viral and bacterial mimics, respectively. The specific stimulations did not affect the self‐renewal and apoptosis capabilities of MSCs but instead promoted their differentiation into the adipocytes and osteoblasts with the TLR3 ligand. The reverse of these results were obtained with the TLR4 ligand. The migration of the MSCs to stimulate either of the two specific ligands was inhibited at different times, whereas the immunogenicity and immunosuppressive properties of the MSCs were not weakened unlike in the MSCs group. These results suggest that TLR3 and TLR4 stimulation affect the characterization of MSCs.     

Toll样受体4信号转导通路的干预

Toll样受体4(Toll like receptor 4,TLR4)是广泛表达于哺乳动物的跨膜受体,由于TLR4在人体的高表达与各种炎症反应相关联,抑制过高的TLR4表达可能是控制机体炎症损伤的新途径.目前的研究主要是针对TLR4的直接阻断与对TLR4的信号转导通路的抑制.由于TLR4的信号转导通路已经较为明确,从而研究对TLR4信号转导通路的抑制可能会对机体过强的炎症反应及损伤的控制产生有益作用.本文就当前针对抑制TLR4信号转导通路的研究作一综述.     

Toll样受体与抗结核感染免疫

结核分枝杆菌(MTB)是结核病的致病菌,其发病机制仍未阐明。Toll样受体(TLR)蛋白家族属于动物模式识别受体家族。研究表明,TLR对先天免疫和获得性免疫都有调控作用,与抗结核感染免疫有关的主要是TLR2和TLR4。对TLR的研究为MTB诱导先天免疫反应机制的阐明以及治疗方法的进步提供了新的思路。     

Toll样受体对T细胞功能及代谢的影响

Toll样受体（Toll-like receptors, TLRs）在先天免疫系统中广泛表达,可通过促进抗原提呈细胞（antigen presenting cells,APC）共刺激分子的表达从而间接导致T细胞活化。然而研究发现,TLR也可在T细胞中表达,并可在没有APC的情况下直接调节T细胞的代谢与功能。本文综述了TLR信号对不同T细胞亚群代谢和免疫功能的直接调控作用,为T细胞介导的癌症及自身免疫病等疾病的预防和治疗提供了新的思路。     

Interleukin‐8 and CXCL10 expression in oral keratinocytes and fibroblasts via Toll‐like receptors

Oral keratinocytes and fibroblasts may be the first line of host defense against oral microorganisms. Here, the contention that oral keratinocytes and fibroblasts recognize microbial components via Toll‐like receptors (TLRs) and participate in development of oral inflammation was examined. It was found that immortalized oral keratinocytes (RT7), fibroblasts (GT1) and primary cells express mRNA of TLRs 1–10. Interleukin‐8 (IL‐8) production by RT7 cells was induced by treatment with TLRs 1–9 with the exception of TLR7 agonist, whereas GT1 cells were induced to produce IL‐8 by all TLR agonists tested except for TLR7 and TLR9. GT1 cells showed increased CXCL10 production following treatment with agonists for TLR1/2, TLR3, TLR4, and TLR5, whereas only those for TLR3 and TLR5 increased CXCL10 production in RT7 cells. Moreover, TLR agonists differentially regulated tumor necrosis factor‐alpha‐induced IL‐8 and CXCL10 production by the tested cell types. These findings suggest that recognition of pathogenic microorganisms in oral keratinocytes and fibroblasts by TLRs may have important roles in orchestrating host immune responses via production of various chemokines.     

Neutralization of pro‐inflammatory monocytes by targeting TLR2 dimerization ameliorates colitis

Monocytes have emerged as critical driving force of acute inflammation. Here, we show that inhibition of Toll‐like receptor 2(TLR2) dimerization by a TLR2 transmembrane peptide (TLR2‐p) ameliorated DSS‐induced colitis by interfering specifically with the activation of Ly6C⁺ monocytes without affecting their recruitment to the colon. We report that TLR2‐p directly interacts with TLR2 within the membrane, leading to inhibition of TLR2–TLR6/1 assembly induced by natural ligands. This was associated with decreased levels of extracellular signal‐regulated kinases (ERK) signaling and reduced secretion of pro‐inflammatory cytokines, such as interleukin (IL)‐6, IL‐23, IL‐12, and IL‐1β. Altogether, our study provides insights into the essential role of TLR2 dimerization in the activation of pathogenic pro‐inflammatory Ly6C^hi monocytes and suggests that inhibition of this aggregation by TLR2‐p might have therapeutic potential in the treatment of acute gut inflammation.