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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 林琬琬(Wan-Wan Lin) | |
dc.contributor.author | Yi-Ting Huang | en |
dc.contributor.author | 黃誼庭 | zh_TW |
dc.date.accessioned | 2021-06-08T02:48:49Z | - |
dc.date.copyright | 2017-09-14 | |
dc.date.issued | 2017 | |
dc.date.submitted | 2017-08-18 | |
dc.identifier.citation | References
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/20441 | - |
dc.description.abstract | 中文摘要
CLEC5A為先天免疫受體中C型凝集素(C-type lectin)受體的一員,並且廣泛的表現在骨髓細胞。過去的研究顯示CLEC5A在登革熱病毒、日本腦炎病毒和流感病毒的感染、類風濕性關節炎和抽菸造成的肺部發炎扮演著重要的角色。在我們的研究使用CLEC5A基因剔除的小鼠,探討CLEC5A在葡聚醣硫酸鈉(DSS)引起的結腸炎和暫時性大腦中動脈阻塞引起的缺血性中風中所扮演的角色。同時,我們使用CLEC5A基因剔除小鼠骨髓衍生的巨噬細胞和微膠細胞,探討CLEC5A對TLR的訊息傳遞和相關發炎基因表現,巨噬細胞極化,以及在微膠細胞對缺氧缺糖再給氧環境所扮演的角色。在葡聚醣硫酸鈉引起的結腸炎的動物疾病模式中,CLEC5A基因剔除可以減輕老鼠腸道出血、腹瀉、體重減輕、組織破壞,以及促炎細胞因子的基因表現。在暫時性大腦中動脈阻塞引起的缺血性中風動物疾病模式中,CLEC5A基因剔除可降低腦部受損面積、神經死亡,以及促炎細胞因子的基因表現。細胞實驗的部分,藉由在骨髓衍生巨噬細胞中加入脂多醣(LPS)和聚肌胞苷酸(polyI:C),我們發現CLEC5A基因剔除可以降低TRIF所調控的TBK1及晚期的IKK-NFB訊息傳遞、第一型干擾素的基因表現及自泌/旁泌作用後的STAT1訊息傳遞活化,但不影響脂多醣所誘導的MyD88訊息傳遞 (如早期IKK-NFB訊息傳遞及MAPKs)及引起的TLR4受體內吞作用。另外在誘導骨髓衍生巨噬細胞成M1或M2極化細胞中,我們發現CLEC5A基因剔除有利於巨噬細胞趨向M2而非M1發展,且對IL-4所引起的JAK1/STAT6訊息傳遞有加強的作用。經由缺氧缺糖及再給氧的處理,CLEC5A基因剔除的微膠細胞表現較少的發炎相關基因。統整以上結果,我們認為CLEC5A與腸道發炎和缺血性中風所引發的腦損傷有關,而其原因可能歸因於CLEC5A對 TLR4/3誘導的TRIF訊息傳遞、發炎反應和巨噬細胞M1極化反應具有正向調控的功能。 | zh_TW |
dc.description.abstract | Abstract
CLEC5A belongs to C-type lectin receptors, a kind of pathogen recognition receptor (PRR) for innate immunity and is widely expressed in myeloid cells. Previous studies indicate that CLEC5A is critical for the pathologies of selected virus infection such as dengue virus, Japanese encephalitis virus and influenza virus, rheumatoid arthritis and cigarette smoke-induced lung inflammation. In this study, we investigated the roles of CLEC5A in the pathological severity of dextran sodium sulfate (DSS)-induced colitis and transient middle cerebral artery occlusion (tMCAO)-induced ischemic stroke in mice. In cell culture studies, we used CLEC5A-/- bone marrow-derived macrophages (BMDM) to determine the roles of CLEC5A in TLR4/3 signaling, macrophage M1/M2 polarization and inflammatory cytokine gene expression under TLRs stimulation. In addition, we used primary microglia to determine the role of CLEC5A in inflammation following oxygen/glucose deprivation. In DSS-induced colitis model, CLEC5A knockout reduced the body weight loss, diarrhea, intestinal bleeding, histological score and pro-inflammatory cytokine gene expressions in colons. In tMCAO-induced ischemic stroke model, CLEC5A knockout ameliorated the infarct volume, neuron death and pro-inflammatory cytokines gene expression in brains. In BMDM stimulated with TLR4 ligand LPS or TLR3 ligand poly(I;C), CLEC5A knockout attenuated the TRIF-dependent activation of TBK1, late phase NFB and p65 nuclear translocation, as well as type I interferon mRNA expression and subsequent autocrine/paracrine effect for STAT1 activation. Nevertheless, CLEC5A knockout did not exhibit the effects on LPS-induced MyD88-dependent signaling pathways, including early phase NFB and MAPKs nor TLR4 endocytosis. Notably, CLEC5A knockout promoted macrophage polarization to M2 but not M1 after treatment with LPS and IFN as M1 stimuli and IL-4 as M2 stimulus, respectively. Supporting this finding, IL-4-induced JAK/STAT6 signaling was enhanced in CLEC5A-/- BMDM. Furthermore, in oxygen-glucose deprivation and re-oxygenation condition, CLEC5A-/- primary microglia showed the lower pro-inflammatory gene expression than WT cells. Altogether, CLEC5A is involved in DSS-induced intestinal inflammation and ischemia-induced brain injury, possibly through the positive regulation of TLRs-induced TRIF signaling pathways, inflammation responses and M1 macrophage polarization. | en |
dc.description.provenance | Made available in DSpace on 2021-06-08T02:48:49Z (GMT). No. of bitstreams: 1 ntu-106-R04443020-1.pdf: 2737482 bytes, checksum: f571832d8871b84cfbf354a987b6a735 (MD5) Previous issue date: 2017 | en |
dc.description.tableofcontents | TABLE OF CONTENTS
口試委員會審定書 ⅰ 誌謝 ii Abstract iii 中文摘要 v Abbreviations vi Introduction 1 I. Innate immunity and pattern recognition receptors 1 1. Innate immunity 1 2. C-type lectin receptors 2 3. CLEC5A 4 4. Toll-like receptor 6 5. Signaling pathways of TLR3 and TLR4 7 6. Crosstalk between CLEC5A and TLRs 9 II. Biological functions and regulation of macrophage polarization 9 III. Colitis and inflammatory bowel disease 10 IV. Stroke 12 1. The classification of stroke 12 2. Pathological mechanisms of ischemic stroke 14 Aim 17 Materials and methods 18 Mice and ethics statement 18 Reagents and antibodies 18 Cell culture of bone marrow-derived macrophages (BMDM) 19 DSS-induced colitis model 20 Bacteremia assay 21 Histological examination of colitis 21 Transient middle cerebral artery occlusion (tMCAO)-induced ischemic stroke 22 Cylinder test 23 Infarct volume measurement 24 Frozen section of mice brain 24 Nissl stain 25 Cell culture of primary microglia 26 Oxygen-glucose deprivation/re-oxygenation (OGD/R) in primary microglia 26 Western blotting of cell lysates, colon and cortical tissues 27 Nuclear and cytoplasmic extraction 28 Reverse-transcription (RT) and real-time polymerase chain reaction (PCR) 29 Flow cytometry 31 ELISA 32 Statistical evaluation and image quantification 32 Results 33 CLEC5A knockout protected mice against DSS-induced colitis 33 CLEC5A knockout reduced LPS-induced inflammatory gene expression in BMDM. 35 CLEC5A knockout did not affect MyD88- but reduced TRIF-dependent pathways of TLR4 and TLR3 36 Differential effects of CLEC5A knockout on macrophage M1/M2 polarization 38 CLEC5A knockout protected mice against ischemia stroke in tMCAO/R model 40 CLEC5A knockout reduced the inflammatory responses of primary microglia in OGD/R condition 41 Discussion 43 Figures and legends 49 References 62 Appendix 70 | |
dc.language.iso | en | |
dc.title | 探討CLEC5A參與巨噬細胞和微膠細胞的發炎反應及對腸炎和缺血性中風的角色 | zh_TW |
dc.title | The roles of CLEC5A in macrophages- and microglia-derived inflammation responses, colitis and ischemic stroke | en |
dc.type | Thesis | |
dc.date.schoolyear | 105-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 謝世良(Shie-Liang Hsieh),符文美(Wen-Mei Fu),蔡丰喬(Feng-Chiao Tsai),曾賢忠(Shiang-Jong Tzeng) | |
dc.subject.keyword | CLEC5A,腸炎,缺血性中風,巨噬細胞,微膠細胞,TLR3,TLR4, | zh_TW |
dc.subject.keyword | CLEC5A,colitis,ischemic stroke,macrophage,microglia,TLR3,TLR4, | en |
dc.relation.page | 74 | |
dc.identifier.doi | 10.6342/NTU201703860 | |
dc.rights.note | 未授權 | |
dc.date.accepted | 2017-08-18 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 藥理學研究所 | zh_TW |
顯示於系所單位: | 藥理學科所 |
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