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研究生：	曾資凱 Tseng, Tsu-Kai
論文名稱：	菸鹼醯胺腺嘌呤二核苷酸磷酸氧化酶缺陷小鼠在塵螨-脂多醣的刺激後經由增加促炎間質巨噬細胞、Siglec-F+嗜中性球和LTi-like第三型自然類淋巴細胞誘發肺纖維化 Der P-LPS stimulation induces more severe lung fibrosis through increased TNF-α-producing M1 interstitial macrophages, Siglec-F-expressing neutrophils and LTi-like type 3 innate lymphoid cells in NOX2-deficient mice
指導教授：	謝奇璋 Shieh, Chi-Chang
學位類別：	碩士 Master
系所名稱：	醫學院 - 微生物及免疫學研究所 Department of Microbiology & Immunology
論文出版年：	2024
畢業學年度：	112
語文別：	英文
論文頁數：	77
中文關鍵詞：	嗜中性白血球、表達Siglec-F 嗜中性白血球、間質巨噬細胞、M1/M2 極化、腫瘤壞死因子、肌成纖維細胞、肺纖維化、LTi 樣ILC3 、白細胞介素-17A
外文關鍵詞：	neutrophils, Siglec-F-expressing neutrophils, interstitial macrophages, M1/M2 polarization, TNF-α, myofibroblasts, lung fibrosis, LTi-like ILC3s, IL-17A
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過敏性氣喘是一種慢性疾病，由免疫細胞引起肺部發炎會導致嗜酸性白血球增多或嗜中性白血球增多。在近半個世紀，發現過敏性氣喘病情的進展可能會導致肺纖維化，但由於肺纖維化的機制尚不明確。根據過去的了解，巨噬細胞和嗜中性白血球在受到脂多醣 (LPS) 或病原體刺激時會產生活性氧化物質 (ROS) 來介導病原體引起的肺部發炎並調控免疫平衡。此外 NADPH 氧化酶2 (NOX2) 的缺陷導致細胞無法產生 ROS，進而使巨噬細胞和嗜中性白血球球失去清除病原體的功能。近年科學家們發現，自然類類淋巴細胞和輔助T細胞類似，可以調控免疫細胞活化和組織發炎。過去的研究顯示，表達 Siglec-F 嗜中性白血球可能透過在人類腎臟中產生 TGF-β、TNF-α 和 IL-1β 去誘導組織纖維化。另一篇研究發現，間質巨噬細胞 (IM) 產生雙調蛋白-1 (Arg-1) 來誘導成纖維細胞的分化和增殖。此外有一篇研究表明，LTi 樣 ILC3 可能透過產生 IL-17A 和 IL-22 來調節組織發炎。先前本實驗室發現，用屋塵蟎（Der P）刺激的 NOX2 缺陷小鼠具有更強的肺部炎症，且觀察到嗜中性白血球和嗜酸性粒細胞浸潤的現象，而這些小鼠有更嚴重的肺纖維化的產生。然而，目前尚不清楚 NOX2 如何影響免疫細胞去誘導肺纖維化。在這篇研究，我們利用 Der P 和 LPS （Der P-LPS）刺激 WT 和 Cybb-/- 雌性小鼠來建立過敏性氣喘模型。首先，我們使用蘇木精和伊紅 (H&E) 染色法和 Masson 三色染色法，確定 Der P-LPS 刺激會導致 Cybb-/- 小鼠具有更嚴重的細胞浸潤和膠原蛋白產生。此外，我們透過肺功能測試證實，Der P-LPS 刺激的 Cybb-/- 小鼠會誘發嚴重的氣道高反應性和肺纖維化。此外，我們檢測整個肺組織中的細胞因子，發現在 Der P-LPS 刺激後，Cybb-/- 小鼠中 TNF-α、IL-1β、IL-4 和 IL-17A 的產量提升。隨後，我們使用流式細胞儀分析肺組織中的顆粒球、巨噬細胞、成纖維細胞和自然類類淋巴細胞 (ILC) 群。結果顯示，Der P-LPS 刺激後，Cybb-/- 小鼠中嗜中性白血球、表達 Siglec-F 嗜中性白血球、間質巨噬細胞和肺泡巨噬細胞 (AM) 的數量均有所增加。此外，當Cybb-/- 小鼠受到 Der P-LPS 刺激時，間質巨噬細胞極化為 M1 表型，而肺泡巨噬細胞則極化為 M2 表型。此外，在 Der P-LPS 刺激的 Cybb-/- 小鼠中，間質巨噬細胞產生 TNF-α 的能力提升，且成纖維細胞會轉分化更多肌成纖維細胞。在自然類淋巴細胞分析結果顯示，與 WT 相比，Der P-LPS 刺激後 Cybb-/- 小鼠中 LTi 樣 ILC3 的數量更多。此外，Cybb-/- 小鼠的ILC2s 中 IL-17A 的產量高於 WT 小鼠，且 LTi 樣 ILC3s 比 ILC3s 具有產生更多 IL-17A 的能力。這些發現顯示，NOX2 缺陷小鼠中的 Der P-LPS 刺激會導致間質巨噬細胞、肺泡巨噬細胞、表達 Siglec-F 嗜中性白血球和 LTi 樣 ILC3 的累積。而這樣的情況下，極化為 M1 表型的間質巨噬細胞可能會產生 TNF-α，進而導致肺纖維化。本研究的結果釐清 NOX2 缺乏所導致自然免疫失調的疾病機轉，並對慢性肉腫病患過敏原誘導的肺纖維化提供重要的線索。

Allergic asthma is a chronic disease, which is induced lung inflammation causing the eosinophilia or neutrophilia. In the past half-century, the disease progression of allergic asthma has often resulted in lung fibrosis, which is difficult to resolve in clinical treatment due to the unclear mechanisms underlying lung fibrosis. Lack of NADPH oxidase 2 (NOX2) results in an inability to produce ROS, which impairs the effector functions of macrophages and neutrophils to remove pathogens. Innate lymphoid cells modulate tissue inflammation and induce the number of immune cells to clear pathogens in innate immune responses. A previous study showed that Siglec-F-expressing neutrophils may induce tissue fibrosis by the production of TGF-β, TNF-α and IL-1β in human kidney. In addition, interstitial macrophages (IMs) produced Amphiregulin-1 (Arg-1) to induce the differentiation and proliferation of fibroblasts. Moreover, LTi-like ILC3s may modulate the tissue inflammation and homeostasis by the production of IL-17A and IL-22. We previously found that NOX2 deficiency stimulated with Dermatophagoides pteronyssinus (Der P) have stronger lung inflammation characterized by infiltration of both neutrophils and eosinophils, and observed more severe lung fibrosis in those mice. However, it remained unclear how NOX2 affect different immune cell populations to induce lung fibrosis. We utilized female mice of WT and Cybb-/- challenged with Der P along with LPS (Der P-LPS) to established the allergic asthma model. Firstly, we identified that Der P-LPS stimulation causes more severe cell infiltration and collagen production, and observe more severe airway hyperreactivity and lung stiffness in Cybb-/- mice. The level of whole lung cytokine found that the production of TNF-α, IL-1β, IL-4, and IL-17A was elevated in Cybb-/- mice following Der P-LPS stimulation. In cell population analysis, we examined the numbers of neutrophils, Siglec-F-expressing neutrophils, IMs, alveolar macrophages (AMs), and LTi-like ILC3s were increased in Cybb-/- mice after Der P-LPS stimulation.In addition, the polarization of IMs to M1 phenotype, and the polarization of AMs to M2 phenotype in Cybb-/- mice. Moreover, the production of TNF-α in IMs were promoted in Der P-LPS- stimulated Cybb-/- mice, and LTi-like ILC3s have greater ability to produce IL-17A than ILC3s. Furthermore, the differentiation of fibroblasts into myofibroblasts were induced in Cybb-/- mice after Der P-LPS stimulation. These findings indicated that Der P-LPS stimulation in NOX2-deficient mice leads to the accumulation of IMs, AMs, Siglec-F-expressing neutrophils, and LTi-like ILC3s. M1-polarized IMs may produce TNF-α, contributing to lung fibrosis. The results from this study shed important light on the role of innate immune cells in allergen-induced pulmonary fibrosis in patients with chronic granulomatous diseases and may provide therapeutic clues for conditions involving NOX2 deficiency in the future.

中文摘要 I
Abstract III
致謝 V
Abbreviations X
Chapter1. Introduction 1
1.1 Asthma as a presentation of allergic inflammation in the lung 2
1.2 The complex of NADPH oxidase 2 associated with the production of reactive oxygen species 2
1.3 The relationship between NADPH oxidase 2 and airway inflammation and pulmonary fibrosis in chronic granulomatous diseases 3
1.4 Fibroblast growth factor (FGF) and TGF-β may contribute to lung fibrosis induced by severe lung inflammation 3
1.5 The granulocytes and macrophages regulate lung fibrosis through the production of inflammatory cytokines 4
1.6 The innate lymphoid cells modulate tissue immune balance through the secretion of type 2 and 3 cytokines 5
1.7 Research rationale 5
Chapter2. Materials Methods and Experiment Design 6
2.1 Animal model experiments 7
2.2 Allergen-stimulated experiments 7
2.3 Measurement of lung function 8
2.4 The tissue section staining and histology examination of the lung 8
2.5 The detection of cytokines by ELISA assay 9
2.6 The populations of pulmonary cells analyzed with flow cytometry 10
2.7 Statistical analyses 11
Chapter 3. Results 12
3.1 Der P-LPS stimulation caused more severe cell infiltration and collagen production in Cybb-/- mice 13
3.2 Der P-LPS stimulation induced airway hyperreactivity and lung fibrosis in Cybb-/- mice 13
3.3 The levels of inflammatory cytokines (including TNF-α, IL-1β, TGF-β and IL-17A) and fibroblast growth factor 2 were elevated in Der P-LPS-induced Cybb-/- mice 14
3.4 The numbers of neutrophils and Siglec-F-expressing neutrophils were increased in Cybb-/- mice following Der P-LPS stimulation 14
3.5 The numbers of interstitial macrophages and alveolar macrophages were higher in Cybb-/- mice after Der P-LPS stimulation when compared with WT 15
3.6 The polarization of interstitial macrophages to M1 phenotype, and alveolar macrophages to M2 phenotype 15
3.7 Der P-LPS-stimulated Cybb-/- mice had higher secretion of TNF-α in interstitial macrophages 16
3.8 The differentiation of fibroblasts into activated myofibroblasts was facilitated in Cybb-/- mice after Der P-LPS stimulation 17
3.9 LTi-like ILC3s was more abundant in Cybb-/- mice after Der P-LPS stimulation when compared with WT	18
3.10 The production of IL-17A in ILC2s was higher in Cybb-/- mice than in WT while LTi-like ILC3s had greater ability to produce IL-17A than other ILC3s 18
Chapter 4. Discussion 20
4.1 Lack of NOX2- derived ROS leads to the activation of neutrophils and Siglec-F-expressing neutrophils to induce lung fibrosis 21
4.2 Lack of NOX2-derived ROS affects the polarization of macrophages relevant for lung inflammation and pulmonary fibrosis 22
4.3 The interaction between Siglec-F-expressing neutrophils and LTi-like ILC3s in allergen-stimulated lung inflammation	23
4.4 The experiment limitation of this study 24
4.5 Conclusion 25
Chapter 5. References 26
Chapter 6. Figure, Legends and Table 32
Figure 1. 33
Figure 1. Der P-LPS-stimulated Cybb-/- mice promoted increased cell infiltration and collagen production when compared with WT.	34
Figure 2. 35
Figure 2. Der P-LPS-stimulated Cybb-/- mice displayed heightened the level of inflammatory cytokines and AHR but decreased the value of the lung compliance. 36
Figure 3. 37
Figure 3. The gating strategy of eosinophils, neutrophils, Siglec-F-expressing neutrophils, interstitial macrophages, alveolar macrophages, fibroblasts and myofibroblasts in lung tissue of both WT and Cybb-/- mice. 38
Figure 4. 39
Figure 4. The numbers of neutrophils and Siglec-F-expressing neutrophils were elevated in Cybb-/- mice following Der P-LPS stimulation.	40
Figure 5. 41
Figure 5. The numbers of interstitial macrophages and alveolar macrophages were promoted in Cybb-/- mice following Der P-LPS stimulation. 42
Figure 6. 43
Figure 6. The gating strategy of the polarization of interstitial macrophages and alveolar macrophages in lung tissue of both WT and Cybb-/- mice. 44
Figure 7. 45
Figure 7. The polarization of interstitial macrophages to M1 phenotype, and the polarization of alveolar macrophages to M2 phenotype in Cybb-/- mice. 46
Figure 8. 47
Figure 8. The numbers of TNF-α and TGF-β production in interstitial macrophages and alveolar macrophages were elevated in Cybb-/- mice following Der P-LPS stimulation. 48
Figure 9. 49
Figure 9. The production of TNF-α in interstitial macrophages was enhanced in Cybb-/- mice following Der P-LPS stimulation. 50
Figure 10. 51
Figure 10. The gating strategy of fibroblasts and myofibroblasts in lung tissue of both WT and Cybb-/- mice. 52
Figure 11. 53
Figure 11. The differentiation of fibroblasts into myofibroblasts was promoted in Cybb-/- mice following Der P-LPS stimulation.	54
Figure 12. 55
Figure 12. The gating strategy of ILC, ILC2, ILC3 and LTi-like ILC3 in lung tissue of both WT and Cybb-/- mice.	56
Figure 13. 57
Figure 13. The number of LTi-like ILC3s was promoted in Cybb-/- mice following Der P-LPS stimulation.	58
Figure 14. 59
Figure 14. The production of IL-17A in ILC2s was increased, and the ability of LTi-like ILC3s to produce IL-17A was higher than that of ILC3s following Der P-LPS stimulation. 60
Figure 15. 61
Figure 15. Der P-LPS-stimulated Cybb-/- mice caused a more severe accumulation of TNF-α-producing M1 IMs, Siglec-F-expressing neutrophils, and LTi-like ILC3s. This accumulation induced the differentiation of fibroblasts into myofibroblasts, resulting in lung fibrosis. 61
Figure 16. 62
Figure 16. The deficiency of NOX2-derived ROS caused IMs to polarize to M1 phenotype, which induces lung fibrosis, while AMs polarize to M2 phenotype. However, we do not yet know how AMs affect lung inflammation. 62
Table 1. Antibodies to identify cell population by flow cytometry analyses 63
                                    

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