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| ???org.dspace.app.webui.jsptag.ItemTag.dcfield??? | Value | Language |
|---|---|---|
| dc.contributor.advisor | 徐立中 | zh_TW |
| dc.contributor.advisor | Li-Chung Hsu | en |
| dc.contributor.author | 江蕙萱 | zh_TW |
| dc.contributor.author | Huei-Syuan Jiang | en |
| dc.date.accessioned | 2021-07-11T15:33:38Z | - |
| dc.date.available | 2024-08-13 | - |
| dc.date.copyright | 2018-09-04 | - |
| dc.date.issued | 2018 | - |
| dc.date.submitted | 2002-01-01 | - |
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The interaction between IKKα and LC3 promotes type I interferon production through the TLR9-containing LAPosome. Sci. Signal. 11, eaan4144 (2018). 76. Lau, C. M. et al. RNA-associated autoantigens activate B cells by combined B cell antigen receptor/Toll-like receptor 7 engagement. J. Exp. Med. 202, 1171-1177 (2005). | - |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/78976 | - |
| dc.description.abstract | 漿狀樹突細胞(plasmacytoid dendritic cells)是一種特化的先天免疫細胞，其在病毒感染時能夠產生大量的第一型干擾素(type I interferons)。 第七型和第九型類鐸受體（Toll-like receptor 7 and 9）在漿狀樹突細胞中高度表現，並且能夠分別偵測單股核糖核酸(single strand RNA)和未甲基化的CpG位點去氧核醣核酸(CpG DNA)。我們先前的研究發現ZNRF1在脂多糖（Lipopolysaccharide）刺激後會增強前發炎激素(pro-inflammatory cytokines)的製造並抑制抗發炎激素 (anti-inflammatory cytokines) 的產生，顯示ZNRF1在第四型類鐸受體(Toll-like receptor 4)主導的免疫反應中具有正向調節功能。然而，ZNRF1在胞內體型類鐸受體主導的免疫反應中所扮演的角色仍不清楚。在這篇研究中，我們顯示當漿狀樹突細胞中的第七型和第九型類鐸受體藉由配體刺激或是病毒感染活化後，ZNRF1缺失會增強第一型干擾素產生而前發炎激素則不受影響。增強的第一型干擾素反應也促進ZNRF1缺失的人類漿狀樹突細胞抵抗第一型單純皰疹病毒(herpes simplex virus 1)感染的能力。此外，ZNRF1的泛素連接酶活性對於其調控第七型類鐸受體主導第一型干擾素的製造是必須的。最後，我們發現ZNRF1缺失會導致IKKα的活性增加，並延遲IKKα和LC3B之間的分離。總結以上，我們的結果顯示ZNRF1在第七型和第九型類鐸受體主導的免疫反應中扮演負向調控的角色，並有可能作為治療第一型干擾素相關自體免疫疾病的新標靶。 | zh_TW |
| dc.description.abstract | Plasmacytoid dendritic cells (pDCs) are a specialized population of innate immune cells, which are capable of producing large amounts of type I interferons (IFNs) following viral infection. Toll-like receptor (TLR) 7 and 9 are highly expressed in pDCs and are able to sense single strand RNA (ssRNA) and unmethylated CpG DNA, respectively. Our previous studies demonstrated that ZNRF1 enhanced the production of pro-inflammatory cytokines and suppressed anti-inflammatory cytokines production after LPS challenge, suggesting its positive regulatory function in TLR4-triggered inflammatory reposes. However, the regulatory role of ZNRF1 in endosomal TLRs-mediated immune responses remains unclear. Here we demonstrated that ZNRF1 deficiency enhanced type I IFNs production whereas the production of pro-inflammatory cytokines remained unaffected in pDCs after TLR7 and TLR9 activation induced by both ligands and virus infection. Consistently, enhanced type I IFNs production in ZNRF1 -/- CAL-1 promoted the host defense against HSV-1 infection. Furthermore, we showed that the E3 ubiquitin ligase activity of ZNRF1 was required for its regulatory function in TLR7-mediated type I IFNs production, which worked through modulating IKKα activity. Finally, immuno-fluorescence images showed that the disassociation of IKKα and LC3B was delayed in ZNRF1 -/- CAL-1. Taken together, our results suggested that ZNRF1 is a negative regulator of TLR7/9-driven immune response in pDCs and may serve as a novel therapeutic target for type I IFNs-mediated autoimmune diseases. | en |
| dc.description.provenance | Made available in DSpace on 2021-07-11T15:33:38Z (GMT). No. of bitstreams: 1 ntu-107-R05448007-1.pdf: 4084649 bytes, checksum: 08388149500afdba40ee55ed49370dc4 (MD5) Previous issue date: 2018 | en |
| dc.description.tableofcontents | 口試委員審定書............................................................................................................... i
致謝.................................................................................................................................. ii 摘要…............................................................................................................................. iii Abstract ........................................................................................................................... iv Contents .......................................................................................................................... vi Introduction ..................................................................................................................... 1 Inflammation ........................................................................................................... 1 Pattern recognition receptors (PRRs) ...................................................................... 1 Toll-like receptors (TLRs) ....................................................................................... 4 TLRs signaling pathways ........................................................................................ 4 Nucleic acid-sensing TLRs ...................................................................................... 5 TLR7/9 and virus ..................................................................................................... 6 TLR7/9 and plasmacytoid dendritic cells (pDCs) ................................................... 6 TLR7/9 signaling pathway ...................................................................................... 7 TLR7/9 Trafficking .................................................................................................. 8 Proteolytic cleavage of TLR7/9 ............................................................................. 11 Ubiquitination ........................................................................................................ 12 Ubiquitination in TLRs-mediated immune responses ........................................... 13 Zinc and RING finger 1 (ZNRF1) ......................................................................... 14 ZNRF1 and immunity............................................................................................. 15 ZNRF family .......................................................................................................... 16 Aim ................................................................................................................................ 18 Materials and Methods .................................................................................................. 19 Reagents and antibodies .........................................................................................19 Preparation of recombinant human FMS-like tyrosine kinase 3 ligand (hFlt3L) .. 21 Mice ....................................................................................................................... 22 Preparation of Flt3L-induced bone marrow-derived pDCs (Flt3L-pDCs) ............ 23 B220-positive selection.......................................................................................... 24 Cell culture and stimulation .................................................................................. 24 Generation of ZNRF1 knockout CAL-1 using CRISPR/Cas9 system and lentiviral infection ................................................................................................. 25 Flow cytometry ..................................................................................................... 26 RNA purification and quantitative RT-PCR (RT-qPCR) ....................................... 27 Cell lysates preparation ......................................................................................... 29 Immunoblotting ..................................................................................................... 30 Immunofluorescence ............................................................................................. 31 Virus amplification ................................................................................................ 32 Plaque assay ........................................................................................................... 33 Generation of Flt3L-derived immortalized hematopoietic stem and progenitor cell (Flt3L-iHPSC) ....................................................................................................... 34 Statistical analysis ..................................................................................................35 Results ............................................................................................................................36 Murine bone marrow cells differentiate into cDCs and pDCs after incubation with Flt3L for 7-9 days .......................................................................................... 37 Homemade recombinant human Flt3L induces differentiation of bone marrows into dendritic cells as efficiently as commercial murine Flt3L ............................. 38 ZNRF1 is not required for pDCs development ..................................................... 39 ZNRF1 depletion enhances type I IFNs but not pro-inflammatory cytokines production upon TLR7 and TLR9 ligand stimulation in Flt3L-pDCs ................... 39 ZNRF1-/- CAL-1 produces higher amount of type I IFNs upon TLR7 Activation .............................................................................................................. 41 ZNRF1 deficiency enhances host defense against HSV-1 infection …................. 41 The catalytic activity of ZNRF1 is required for its regulatory function in TLR7-triggered type I IFNs production ................................................................ 42 ZNRF1 deficiency enhances IKKα activation upon TLR7 activation in CAL-1 cells ........................................................................................................................ 43 ZNRF1 deficiency has little influence on the canonical NF-κB activation triggered by TLR7 activation ................................................................................................ 45 Znrf1+/+ and Znrf1-/- Flt3L-immortalized hematopoietic stem and progenitor cells (iHPSCs) showed similar morphology and differentiation capability .................. 47 Discussion ..................................................................................................................... 49 The possible role of ZNRF1 in TLR7 and TLR9 trafficking................................. 51 The possible role of ZNRF1 in regulation of IKKα activity.................................. 53 The possible role of ZNRF1 in the interaction between IKKα and LC3B ............ 54 The possible role of ZNRF1 in type I IFNs-related autoimmune diseases ........... 56 Figures ........................................................................................................................... 57 Figure 1. Murine bone marrow cells differentiate into cDCs and pDCs after incubation with Flt3L for 7-9 days ................................................................ 57 Figure 2. Homemade recombinant human Flt3L induces bone marrow differentiation into dendritic cells as efficient as commercial murine Flt3L ......... 58 Figure 3. ZNRF1 depletion doesn’t affect bone marrow derived dendritic cells (BMDCs) development ................................................................................. 60 Figure 4. The purity of pDCs population can reach 70-80% after positive selection of B220+ Flt3L-BMDCs ........................................................................................ 62 Figure 5. ZNRF1 is not involved in pDC development ........................................ 63 Figure 6. ZNRF1 depletion enhances the production of type I IFNs but not pro-inflammatory cytokines upon TLR7 ligand stimulation in Flt3L-pDCs ......... 64 Figure 7. ZNRF1 depletion enhances the production of type I IFNs but not pro-inflammatory cytokines upon TLR9 ligand stimulation in Flt3L-pDCs ......... 65 Figure 8. ZNRF1 depletion enhances type I IFNs production in Flt3L-pDCs after influenza A infection ..................................................................................... 66 Figure 9. ZNRF1 depletion enhances type I IFNs in Flt3L-pDCs after HSV-1 infection ..................................................................................................... 68 Figure 10. Generation of ZNRF1-/- CAL-1 cells by CRISPR/Cas9 system ........... 70 Figure 11. ZNRF1-deficient CAL-1 cells produce increased type I IFNs upon TLR7 activation ............................................................................................ 71 Figure 12. ZNRF1 deficiency enhances host defense against HSV-1 infection .... 73 Figure 13. ZNRF1-mediated R848-induced type I IFNs production is required it E3 ubiquitin ligase ............................................................................... 75 Figure 14. ZNRF1 deficiency enhances IKKα activation in CAL-1 after challenge with R848 .......................................................................................76 Figure 15. ZNRF1 deficiency in CAL-1 cells enhances STAT1 activation and the expression of interferon-stimulated gene OAS1 after R848 stimulation ............... 77 Figure 16. ZNRF1 deficiency in CAL-1 cells has little impact on the canonical NF-κB activation upon TLR7 activation ............................................................... 79 Figure 17. ZNRF1 deficiency in CAL-1 cells delays the disassociation of IKKα and LC3B................................................................................................................ 80 Figure 18. Znrf1-/- Flt3L-iHPSCs showed similar morphology and differentiation ability as WT Flt3L-iHPSCs ......................................................... 83 Figure 19. The proposed model summarizing the regulation of TLR7/9-mediated immune responses by ZNRF1 in pDCs ................................................................. 85 References ..................................................................................................................... 86 | - |
| dc.language.iso | en | - |
| dc.subject | 泛素連接? | zh_TW |
| dc.subject | 第七型類鐸受體 | zh_TW |
| dc.subject | 漿狀樹突細胞 | zh_TW |
| dc.subject | 第九型類鐸受體 | zh_TW |
| dc.subject | pDCs | en |
| dc.subject | TLR7 | en |
| dc.subject | TLR9 | en |
| dc.subject | ZNRF1 | en |
| dc.title | ZNRF1在TLR7/9主導之免疫反應中所扮演的角色 | zh_TW |
| dc.title | The Regulatory Role of ZNRF1 in TLR7/9-mediated Immune Responses | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 106-2 | - |
| dc.description.degree | 碩士 | - |
| dc.contributor.oralexamcommittee | 劉旻禕;黃麗華 | zh_TW |
| dc.contributor.oralexamcommittee | Helene Minyi Liu;Lih-Hwa Hwang | en |
| dc.subject.keyword | 第七型類鐸受體,第九型類鐸受體,漿狀樹突細胞,泛素連接?, | zh_TW |
| dc.subject.keyword | TLR7,TLR9,pDCs,ZNRF1, | en |
| dc.relation.page | 92 | - |
| dc.identifier.doi | 10.6342/NTU201803726 | - |
| dc.rights.note | 未授權 | - |
| dc.date.accepted | 2018-08-16 | - |
| dc.contributor.author-college | 醫學院 | - |
| dc.contributor.author-dept | 分子醫學研究所 | - |
| dc.date.embargo-lift | 2028-08-15 | - |
| Appears in Collections: | 分子醫學研究所 | |
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