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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/8183Full metadata record
| ???org.dspace.app.webui.jsptag.ItemTag.dcfield??? | Value | Language |
|---|---|---|
| dc.contributor.advisor | 徐立中 | |
| dc.contributor.author | Chi-An Lu | en |
| dc.contributor.author | 盧麒安 | zh_TW |
| dc.date.accessioned | 2021-05-20T00:49:41Z | - |
| dc.date.available | 2025-08-19 | |
| dc.date.available | 2021-05-20T00:49:41Z | - |
| dc.date.copyright | 2020-09-10 | |
| dc.date.issued | 2020 | |
| dc.date.submitted | 2020-08-18 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/8183 | - |
| dc.description.abstract | 漿狀樹突細胞 (plasmacytoid dendritic cells)是哺乳類先天免疫系統中一群扮演哨兵角色的細胞，它們高度表現第七型及第九型類鐸受體 (Toll-like receptor 7 and 9)，此二類鐸受體能分別偵測單股核糖核酸 (single-strand RNA)及未甲基化的CpG位點去氧核糖核酸 (CpG DNA)。當第七型及第九型類鐸受體偵測到配體後，漿狀樹突細胞會立即產生大量的第一型干擾素 (type Ι interferons)來抑制病毒的複製並且促進周圍細胞的抗病毒功能。ZNRF1 (Zinc and ring finger 1)是一種E3泛素連接酶，過去被報導在瓦氏退化現象 (Wallerian degeneration)中扮演重要角色。我們實驗室先前的研究發現ZNRF1在第四型類鐸受體 (Toll-like receptor 4)的活化下會增加促發炎細胞激素 (pro-inflammatory cytokine)並減少抗發炎細胞激素中的白血球介白素-10 (interlukin 10 )，顯示ZNRF1在第四型類鐸受體所誘導的發炎反應中扮演正向調節的角色。我們也進一步發現，當類FMS的酪氨酸激酶-3受體所分化的漿狀樹突細胞(Flt3L-driven pDCs)及人類的漿狀樹突細胞株 (CAL-1)中的第七型及第九型類鐸受體活化後，ZNRF1缺失會增強第一型干擾素產生。在這篇研究中，我們試圖去探討在第七型及第九型類鐸受體所誘導的免疫反應中，ZNRF1的詳細調控機制以及在此過程中ZNRF1是如何被活化。我們首先確認用第七型及第九型類鐸配體刺激人類的漿狀樹突細胞株 (CAL-1)後，ZNRF1缺失會增強第一型干擾素產生。在ZNRF1缺失的人類漿狀樹突細胞株 (CAL-1)中，第七型類鐸受體的活化會增加IKKα、MAPK及IKKβ/NF-κB的活化，而第九型類鐸受體的活化僅會增加的活化。此外，在ZNRF1 103號的酪氨酸對於第七型及第九型類鐸受體所誘導的免疫反應是重要的。我們的動物實驗結果顯示在流感病毒H5N1的感染下IKKα，ZNRF1缺失的小鼠相較於野生型小鼠表現更高的存活率。在流感病毒H5N1感染後第六天，ZNRF1缺失小鼠肺臟中的促發炎細胞激素、第一型干擾素、趨化介素及病毒的mRNA都有較低的情形。然而，究竟ZNRF1缺失在小鼠身上會影響病毒的清除還是細胞激素的產生仍有待之後的實驗釐清。總結以上，我們的結果顯示在漿狀樹突細胞中，ZNRF1可能會透過控制類鐸受體的運輸而負向調節第七型及第九型類鐸受體所驅動的免疫反應。 | zh_TW |
| dc.description.abstract | Plasmacytoid dendritic cells (pDCs), a unique sentinel cell population in the mammalian innate immunity system, express high levels of endosomal Toll-like receptors (TLRs) TLR7 and TLR9, which sense single-strand RNA (ssRNA) and unmethylated CpG DNA, respectively. Upon engagement of TLR7 and TLR9, pDCs produce massive quantities of type Ι interferons (IFNs) rapidly to inhibit viral replication and promote the antiviral functions in surrounding cells. Zinc and ring finger 1 (ZNRF1) is an E3 ubiquitin ligase, which plays a crucial role in Wallerian degeneration. Previous study in our lab demonstrated that ZNRF1 enhanced the production of pro-inflammatory cytokines and reduced anti-inflammatory cytokine IL-10 upon TLR4 activation, suggesting its positive regulatory role in TLR4-triggered inflammatory response. We further demonstrated that ZNRF1 depletion enhanced type interferons in both FMS-like tyrosine kinase 3 ligand (Flt3L)-driven pDCs and CAL-1 cells (human pDCs) upon TLR7 and TLR9 activation. In this study, we aim to reveal the detailed mechanism by which ZNRF1 regulates TLR7- and TLR9-mediated immune responses and how ZNRF1 is activated upon engagement of TLR7 and TLR9. We confirmed that ZNRF1 depletion enhanced type Ι interferon production in CAL-1 cells after stimulation of TLR7 and TLR9 ligands. Activation of IKKα, MAPKs and IKKβ/NF-κB was increased in ZNRF1-depeleted CAL-1 cells after TLR7 engagement. However, only increased IKKα activation was observed in ZNRF1 depletion cells after TLR9 activation. In addition, tyrosine phosphorylation site ZNRF1 on residue 103 is required for TLR7- and TLR9-mediated immune responses. Furthermore, our results showed that ZNRF1 knockout mice displayed better survival compared with wildtype mice after challenged with H5N1 influenza virus (IAV). Lower levels of pro-inflammatory cytokine, type Ι interferons, chemokines and viral mRNA were decreased in Znrf1-/- lungs at day 6 after intratrachea infection of H5N1 IAV. Nevertheless, it remains to be further investigated whether depletion of ZNRF1 in mice affects viral clearance or cytokine production. Taken together, our results suggest that ZNRF1 is a negative regulator of TLR7- and TLR9-driven immune response in pDCs possible through controlling receptor trafficking. | en |
| dc.description.provenance | Made available in DSpace on 2021-05-20T00:49:41Z (GMT). No. of bitstreams: 1 U0001-1608202016231600.pdf: 4794813 bytes, checksum: 49a94a23f61b5678f5f60b8a2b5e5154 (MD5) Previous issue date: 2020 | en |
| dc.description.tableofcontents | 致謝 i 摘要 ii Abstract iv Contents vi Introduction 1 Inflammation 1 Pattern-recognition receptors (PRRs) 1 Toll-like receptors (TLRs) 3 TLRs signaling pathway 4 Nucleic acid-sensing TLRs 5 TLR7/9 in antiviral immunity 6 TLR7/9 signaling pathway in pDCs 6 Type Ι interferon signaling 8 TLR7/9 trafficking 8 Proteolytic cleavage of TLR7/9 11 Ubiquitination 12 Ubiquitination in TLR-mediated immune responses 13 Zinc and RING finger 1 (ZNRF1) 14 ZNRF1 and immunity 16 Aim 17 Material and Methods 18 Reagents and antibodies 18 Mice 19 Preparation of Flt3L-induced bone marrow-derived pDCs (Flt3L-pDCs) 20 Preparation of Flt3L-pDCs 21 Cell culture 22 Generation of ZNRF1 knockout CAL-1 cells using CRISPR/Cas9 system 22 Genomic DNA extraction and sequence alignment 23 RNA extraction and quantitative RT-PCR (RT-qPCR) 24 Cell lysates preparation 28 Immunoblotting 29 Ligand internalization assay 30 Immunoprecipitation 30 Ubiquitination assay 31 Cytosolic and nuclear extract fractionation 31 Virus amplification 32 Intratracheal instillation 33 Infiltrating cells isolation 34 Statistical analysis 35 Results 36 ZNRF1 depletion in Flt3L-pDCs enhances the production of type Ι IFNs and pro-inflammatory cytokines upon TLR7 and TLR9 activation 36 ZNRF1 depletion promotes increased amount of type Ι IFNs in CAL-1 upon TLR7 activation 36 ZNRF1 depletion enhances IKKα activation and nuclear translocation of IRF7 upon TLR7 activation in CAL-1 cells. 37 ZNRF1 depletion promotes TLR7-induced MAPK and IKKβ/NF-κB activation in CAL-1 cells. 40 ZNRF1 Y103 residue is important for its regulatory function in TLR7 signaling 40 ZNRF1 depletion promotes increased amount of type Ι IFNs in CAL-1 upon TLR9 activation. 41 ZNRF1 depletion enhances IKKα activation and nuclear translocation of IRF7 but has little impact on MAPK activation upon TLR9 activation in CAL-1 cells. 42 ZNRF1 Y103 residue is important for its regulatory function in TLR9 signaling 43 ZNRF1 deficient mice are resistant to H5N1 influenza A virus infection. 43 Discussion 45 The possible role of ZNRF1 in TLR7 and TLR9 trafficking 45 The possible role of ZNRF1 in ubiquitination of TLR7/9 47 The possible role of phosphorylation at Y103 of ZNRF1 in TLR7- and TLR9-induced signaling pathway 48 The possible role of ZNRF1 during H5N1 influenza virus infection 49 Figures 51 Figure 1. ZNRF1 depletion enhances TLR7-triggered type Ι IFNs and pro-inflammatory cytokines in Flt3L-pDCs 51 Figure 2. ZNRF1 depletion enhances TLR9-triggered type Ι IFNs and pro-inflammatory cytokines in Flt3L-pDCs 52 Figure 3. Generation of ZNRF1-/- CAL-1 cells by CRISPR/Cas9 system 53 Figure 4. Depletion of ZNRF1 enhances TLR7-induced type Ι IFNs and pro-inflammatory cytokines in CAL-1 cells 54 Figure 5. ZNRF1 deficiency enhances IKKα activation in CAL-1 cells after stimulation with R848 55 Figure 6. ZNRF1 deficiency increases IRF7 activation in CAL-1 cells after stimulation with R848 56 Figure 7. ZNRF1 deficiency in CAL-1 cells enhances STAT1 activation and the expression of interferon-stimulated genes CXCL10 and OAS1 after stimulation with R848 57 Figure 8. ZNRF1 is not involved in the type Ι IFN signaling pathway. 59 Figure 9. ZNRF1 deficiency enhances MAPK activation in CAL-1 cells after stimulation with R848 61 Figure 10. ZNRF1 Y103 is critical for TLR7-induced IKKα, MAPKs and IKKβ/NF-κB activation 63 Figure 11. ZNRF1 depletion induced TLR9-driven type Ι IFNs but not pro-inflammatory cytokines production in CAL-1 cells 64 Figure 12. ZNRF1 deficiency promotes IKKα activation in CAL-1 cells after TLR9 activation 65 Figure 13. ZNRF1 deficiency enhances IRF7 activation in CAL-1 cells after stimulation with CpGA 66 Figure 14. ZNRF1 deficiency in CAL-1 cells enhances STAT1 activation and the expression of interferon-stimulated genes CXCL10 and OAS1 upon TLR9 activation 67 Figure 15. ZNRF1 deficiency in CAL-1 cells has little impact on MAPK activation after stimulation with CpGA 69 Figure 16. Y103 of ZNRF1 is critical for TLR9-induced IKKα and AKT activation 71 Figure 17. Znrf1-/- mice are more resistant to H5N1 influenza virus infection. 72 Figure 18. Znrf1-/- mice displayed reduced levels of pro-inflammatory cytokines and chemokines after H5N1 influenza virus infection 75 Figure 19. Znrf1-/- mice showed reduced numbers of alveolar macrophages, conventional DCs and neutrophils in lungs after influenza virus H5N1 infection 77 Figure 20. The proposed model for the regulation of TLR7 and TLR9-mediated immune response by ZNRF1 in pDCs. 78 References 80 | |
| dc.language.iso | en | |
| dc.title | E3泛素連接酶ZNRF1調控TLR7及TLR9訊息傳遞之研究 | zh_TW |
| dc.title | Study on the Regulation of E3 Ubiquitin Ligase ZNRF1 in the TLR7- and TLR9-mediated Signaling Pathways | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 108-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 顧家綺,劉旻禕 | |
| dc.subject.keyword | 第一型鋅暨環指泛素連接酶,漿狀樹突細胞,第七型類鐸受體,第九型類鐸受體,第一型干擾素,流感病毒, | zh_TW |
| dc.subject.keyword | Zinc and ring finger 1,plasmacytoid dendritic cell,Toll-like receptor 7,Toll-like receptor 9,type Ι interferon,influenza virus, | en |
| dc.relation.page | 95 | |
| dc.identifier.doi | 10.6342/NTU202003587 | |
| dc.rights.note | 同意授權(全球公開) | |
| dc.date.accepted | 2020-08-18 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 分子醫學研究所 | zh_TW |
| dc.date.embargo-lift | 2025-08-19 | - |
| Appears in Collections: | 分子醫學研究所 | |
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