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研究生：	張育銜 Chang, Yu-Hsien
論文名稱：	介白素十七在雷射誘導的脈絡膜血管新生之老鼠模式中的保護性作用 The protective effect of IL-17A in laser-induced choroidal neovascularization mouse model
指導教授：	許育祥 Hsu, Yu-Hsiang
學位類別：	碩士 Master
系所名稱：	醫學院 - 臨床醫學研究所 Institute of Clinical Medicine
論文出版年：	2020
畢業學年度：	108
語文別：	英文
論文頁數：	59
中文關鍵詞：	老年性黃斑部病變、介白素十七、細胞激素、脈絡膜血管新生、氧化壓力
外文關鍵詞：	Age-related macular degeneration (AMD), Interleukin-17A, Cytokines, choroidal neovascularization (CNV), Oxidative stress.
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老年性黃斑部病變是導致老年人口失明的主要原因之一，在臨床上分為乾性與濕性的病變。濕性黃斑部病變主要病徵為脈絡膜的新生血管，其特徵為血管從脈絡膜增生並進入視網膜，這些血管會因為血液的滲漏，進而導致中央視力的缺失。抑制血管新生因子的標靶藥物是目前治療濕性黃斑部病變的主要方式之一，然而近期文獻指出長期抑制血管新生因子的產生，可能會導致視網膜內的神經細胞死亡。介白素十七(Interleukin-17A; IL-17A)為多功能性的細胞激素，它在宿主防禦病原體中有著至關重要的作用。過去文獻顯示黃斑部病變病患血清相較於健康人血清中有表達較高的IL-17A，但IL-17A在老年性黃斑部病變之病理機制中的功能並不明確，因此我的研究將聚焦探討IL-17A在老年性黃斑部病變中扮演的角色。我們建立雷射誘導的脈絡膜血管新生之疾病小鼠模式，利用免疫螢光染色及流式細胞儀分析發現疾病小鼠中表達高量的IL-17A在雷射所誘導之眼睛患部區域。在此疾病模式，運用螢光血管造影分析發現IL-17A基因剔除鼠具有較大範圍的新生血管區域。在流式細胞儀分析中發現IL-17A基因剔除鼠相對於野生型小鼠，會影響適應性免疫細胞的族群並且增加巨噬細胞浸潤至視網膜內的數量。即時聚合酶連鎖反應分析發現IL-17A基因剔除鼠相對於野生型小鼠，視網膜中會有較多的促發炎性細胞因子IL-6。在體外細胞實驗中，我們發現IL-17A透過Nrf2路徑來誘導抗氧化蛋白HO-1的表達。IL-17A也可以減緩由氧化壓力所引起的屏障功能損害。我們實驗結果證明IL-17A在雷射所誘導的脈絡膜血管新生疾病模式中可以扮演著保護性的角色。此研究的發現將對未來老年性黃斑部病變的治療提供新的機制與方向。

Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss in the elderly. The two clinical classifications of AMD are dry and wet AMD. Wet AMD is associated with choroidal neovascularization (CNV), which is characterized by the proliferation of blood vessels that eventually leak fluid, leading to central vision loss. Anti-VEGF therapy has become a standard treatment for wet AMD. However, recent study indicated that long-term VEGFA inhibition may cause retinal cell death. Interleukin-17A (IL-17A), a pleiotropic cytokine secreted primarily by Th17 cells, has been proved to be involved in the microenvironment of certain autoimmune diseases. Previous studies indicated that the serum IL-17A level is higher in AMD patients than in healthy individuals. However, the effect and mechanism of IL-17A in AMD progression are still unknown. In this study, we aimed to investigate how IL-17A regulates choroidal neovascularization development and verify the effects of IL-17A in laser-induced CNV mouse model, which mimicked wet AMD disease. Immunofluorescence staining and fluorescence-activated cell sorting (FACS) analysis showed that higher level of IL-17A was detected in the retina-choroidal region of mice in laser-induced CNV model. Fluorescence angiography analysis showed that IL-17A deficiency mice had larger CNV lesions compared with wildtype (WT) mice in laser-induced CNV model. FACS also showed that IL-17A deficiency influenced the adaptive immunity cell population and increased macrophage infiltration into retina after laser injury. After laser, the expression of IL-6 was elevated in eyes of IL-17A deficiency mice compared with in the WT mice. In vitro, IL-17A induced antioxidant protein HO-1 through regulating Nrf-2 pathway. IL-17A facilitated the repairment of oxidative stress-induced barrier dysfunction. Taken together, our findings provide a new insight into the protective mechanisms of IL-17A that might serve as therapeutic targets for treating wet AMD.

I. 中文摘要  I
II. Abstract  II
III. Acknowledgement  IV
IV. Abbreviation  V
V. Content  VI
VI. Introduction  1
1. Aged-related macular degeneration (AMD)  1
2. Retinal structure  3
3. Blood retinal barrier (BRB)  4
4. Oxidative stress  4
5. Cytokine  5
6. Interleukin-17A (IL-17A)  6
7. Role of IL-17A in the ocular disease  7
8. Laser-induced CNV mouse model  7
VII. Research motivation  9
VIII. Materials and Methods  10
1. Animal  10
2. Laser-induced CNV mouse model and fluorescence angiography 10
3. Isolation of ocular-infiltrating cells, splenocyte, and lymphocyte  10
4. Fluorescence-activated cell sorting (FACS) analysis and detection of cytokine-expressing lymphocytes  11
5. H&E staining and immunofluorescence staining  12
6. RNA extraction and reverse-transcription-RCR (RT-PCR)  12
7. Quantification Real Time PCR (RT-qPCR)  13
8. Western blotting  13
9. Cell culture  14
10. Treatment in retinal pigment epithelial cell line  14
11. Cell viability assay  15
12. Permeability assay  15
13. Statistical analysis  15
IX. Results  16
1. IL-17A was expressed on CNV lesion in laser-induced CNV mouse model  16
2. IL-17A deficiency exacerbated severity in laser-induced CNV mouse model  16
3. IL-17A deficiency couldn’t influence VEGFA expression in laser-induced CNV mouse model  17
4. Th17 cells were the main cellular source of IL-17A in laser-induced CNV mouse model 17
5. IL-17A-deficiency influenced T-reg, Th17, and γδ-T cell populations in the eyes but not in cervical lymph nodes  18
6. IL-17A-deficiency increased macrophage infiltration into the eyes  19
7. The gene expression of inflammatory cytokine in eyes of WT and IL-17A-deficiency mice after laser injury  19
8. IL-17A couldn’t influence the cell viability in ARPE-19 cells  20
9. IL-17A induced antioxidant protein HO-1 through Nrf-2 pathway  20
10. IL-17A facilitated the repairment of oxidative stress-induced barrier dysfunction  21
X. Discussion  22
XI. Tables  27
Table 1. Mouse primer sequences used for RT-qPCR  27
Table 2. Human primer sequences used for RT-qPCR  28
XII. Figures and figure legends  29
Figure 1. IL-17A expressed on CNV lesion in laser-induced CNV mouse model. 30
Figure 2. IL-17A deficiency exacerbated severity in laser-induced CNV mouse model.  31
Figure 3. IL-17A deficiency caused larger damage area on retinal structure in laser-induced CNV mouse model. 32
Figure 4. IL-17A deficiency couldn’t influence VEGFA expression in laser-induced CNV mouse model.  34
Figure 5. Cellular source of IL-17A in the laser-induced CNV mice. 36
Figure 6. IL-17A-deficiency couldn’t influence the cell population of T-reg, Th17 and γδ-T cells in the cervical lymph nodes.  38
Figure 7. IL-17A-deficiency influenced the cell population of T cells, T-reg, Th17 and γδ-T cells in the eyes.  40
Figure 8. IL-17A-deficiency increased macrophage infiltration into the eyes.  41
Figure 9. 7. The gene expression of inflammatory cytokine in eyes of WT and IL-17A-deficiency mice after laser injury.  42
Figure 10. IL-17A didn’t influence the cell viability in ARPE-19 cells. 43
Figure 11. IL-17A induced antioxidant protein HO-1 through Nrf-2 pathway.  45
Figure 12. IL-17A facilitated the repairment of oxidative stress-induced barrier dysfunction.  47
Figure 13. Working model of IL-17A in laser-induced CNV mouse model.  48
XIII. References  49
                                    

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校內：2025-08-31公開
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