臺灣博碩士論文加值系統

根據美國腎臟病數據統計局(USRDS，2004)顯示，2002年台灣地區在20~44歲族群其末期腎臟疾病發生率與盛行率均為全球第三名，其中平均每百萬人中有1800—1900人口罹患慢性腎臟病並接受透析治療，高居全球首位。本研究旨在探討不同單核細胞來源的巨噬細胞，轉化成損傷與修復的M1及M2表型，在慢性腎臟病的炎症致病機轉中所扮演的角色。在2000年新發現的一種免疫球蛋白超家族，髓细胞觸發受體-1（triggering receptors expressed on myeloid cells-1，TREM-1），表達於中性粒细胞、成熟的單核细胞及巨噬细胞表面，在急性炎性疾病如敗血症、急性肺部感染及炎症性腸病的天然免疫和獲得性免疫方面都扮演相當重要的角色。我們首次發現髓细胞觸發受體-1參與腎臟免疫的炎症反應並調控不同亞型的巨噬細胞(M1/M2)轉換。在單側輸尿管阻塞(unilateral ureteral obstruction， UUO) 的腎臟纖維化動物模式實驗中，誘發阻塞性傷害後的7天及14天髓细胞觸發受體-1的訊息核糖核酸表現量有顯著性增加。因此，我們更進一步利用髓细胞觸發受體-1基因缺陷(TREM-1-/-)小鼠，評估發炎反應導致的腎臟纖維化動物模式中，髓細胞觸發受體-1在其中所扮演的角色。首先，在髓细胞觸發受體-1基因缺陷小鼠中，儘管因阻塞性所造成腎臟間質巨噬細胞浸潤數量與野生型小鼠比較無顯著性差異，然而，在腎小管細胞傷害及腎小管間質纖維化程度，基因缺陷小鼠組別與野生型比較有統計學上的減緩。因此，我們更進一步探討髓细胞觸發受體-1基因缺陷小鼠中，腎臟組織傷害的減緩是否因為其中不同亞型的巨噬細胞M1/M2轉變所致，利用免疫组織化學的方法，我們發現在野生型小鼠中大量的誘發型一氧化氮合成酶(inducible nitric oxide synthesis， iNOS)表現於腎小管周邊組織及間質細胞中，同時，M2巨噬細胞亞型標誌精氨酸酶(Arg-1)則是大量出現在髓细胞觸發受體-1基因缺陷小鼠間質中的浸潤細胞，而且利用即時定量反轉錄聚合酵素連鎖反應(Real-Time PCR)方法，在基因缺陷小鼠組別中，M1亞型之相關標誌基因TNF-α，IL-1β和IL-6與野生型小鼠比較有顯著性下降，另外，M2亞型之相關標誌基因Arg-1和IL-10，在基因缺陷小鼠組別中與野生型小鼠比較則是有顯著性上升。然而，目前現今對於髓细胞觸發受體-1研究受限於其所調控受質(ligand)尚未被清楚定義出來，我們在此次實驗中首次發現，髓细胞觸發受體-1在腎阻塞性動物模式中大量表現，其中腎臟會不會就含有我們有興趣未知的细胞觸發受體-1結合物，接下來的實驗利用小鼠阻塞7天及14天腎臟組織均質液，在細胞實驗中誘發骨髓來源的巨噬細胞其細胞激素(cytokine)的釋放，發現在刺激24小時候後，野生型骨髓來源的巨噬細胞其细胞觸發受體-1高度表達並調控下游GM-CSF基因表現，另外，在M1亞型之相關標誌基因iNOS，TNF-α和IFN-gamma與野生型小鼠比較，在基因缺陷小鼠組別則有顯著性下降，而且也發現在相同條件狀況處理下的基因缺陷小鼠其骨髓來源的巨噬細胞，M2亞型之標誌基因Arg-1則有顯著性增加，我們更進一步在細胞中和性抗體實驗當中，將腎臟阻塞組織均質液誘發之下游細胞激素包括：GM-CSF和IFN-gamma中和掉，使得野生型骨髓來源的巨噬細胞趨化成M1亞型的能力也消失掉。最後，在臨床組織標本的分析當中，病患因阻塞性尿道疾病所造成的腎臟損傷當中，细胞觸發受體-1高度表達於受損之腎臟間質巨噬細胞上，並和腎功能損傷的程度與腎臟纖維化形成的程度呈正相關關係。

Monocyte-derived macrophage infiltration of kidney interstitium is a common pathogenic feature of chronic kidney disease (CKD). Distinct classically (M1) and alternatively (M2) activated macrophages have been synonymous with tissue injury and repair, respectively. Cumulative data have demonstrated that triggering receptor expressed on myeloid cells-1 (TREM-1) is a novel receptor constitutively expressed on most monocytes/macrophages. In the present study, we elucidated as to whether TREM-1 involves in renal inflammatory reaction and contributes to diverse macrophages phenotype transition. In vivo, mice of unilateral ureteral obstruction (UUO), a well-established CKD model, were used to explore the mechanism of progression of renal failure. The mRNA levels of TREM-1 up-regulated significantly at 7 and 14 d after UUO. We further performed UUO in TREM-1-/- mice to assess the potential role of TREM-1 in renal inflammation. In TREM-1-/- mice, tubular injury and interstitial collagen deposition were significantly decreased in UUO renal cortex stained with periodic acid-Schiff (PAS) and Masson trichrome as compared to WT mice, despite a similar infiltration of F4/80-positive macrophages between these two groups. In analyzing the markers of mRNA expression for activated macrophages after UUO, we found that inducible nitric oxide synthase (M1 markers) and pro-inflammatory cytokines like TNF-α, IL-1β and IL-6 were significantly decreased, and arginase-1, MR, Ym1 and IL-10 (M2 markers) mRNA expression were significantly increased in TREM-1-/- mice. We hypothesized that after UUO-injured kidney would contain an unknown TREM-1 ligand(s) which may mediate, notably in monocytes/macrophages, the M1 versus M2 polarization. Bone marrow-derived macrophages (BMDM) were obtained from bone marrow of femurs of WT or TREM-1-/- male mice and differentiated with macrophage colony stimulating factor (M-CSF) in vitro. Interesting, co-incubating soluble tissue lysates prepared from UUO-affected WT kidneys triggered M1 differentiation in WT bone marrow-derived macrophages but not in TREM-1 KO cells in vitro. Furthermore, in the study of neutralization, modulation of the expression of GM-CSF and IFN-gamma in BMDM by WT UUO 14 d soluble tissue lysates treatment which promote characteristics of M1 macrophages by production of iNOS. Correspondingly, clinical analysis on specimens collected from UUO nephritis patients also demonstrated a strong correlation between TREM-1 expression, macrophage infiltration, iNOS levels and the severity of renal damage. In summary, TREM-1 is a crucial factor induced in UUO nephritis which contributes to the pathogenic inflammation through the induction of type I macrophage differentiation.

論文電子檔著作權授權書 i
國立陽明大學碩士學位論文審定同意書 ii
Acknowledgements iii
中文摘要 vi
Abstract viii
Table of Contents x
List of Tables xii
List of Figures xiii
1 Introduction 1
1.1 Chronic kidney disease 1
1.2 Obstructive nephropathy 1
1.3 Inflammation on structural and functional renal damage 2
1.4 Unilateral ureteral obstruction (UUO) model 3
1.5 Interstitial macrophages as regulators of inflammatory and fibrotic processes in obstructive nephropathy 4
1.6 TREM-1: an amplifier of acute inflammation 6
2 Hypothesis and specific aims of this study 8
3 Materials and methods 9
3.1 Animals 9
3.2 Experimental UUO animal model 9
3.3 Pathological examinations of the kidneys 9
3.4 Immunohistochemical staining 11
3.5 Immunofluorescence assay 11
3.6 RNA isolation and real-time quantitative RT-PCR 12
3.7 Western blot analysis 13
3.8 Bone marrow cell isolation 13
3.9 Preparation of tissue extraction 14
3.10 Antibody neutralization studies 15
3.11 Statistical analysis 15
4 Results 16
4.1 TREM-1 expression in UUO kidney after obstructive injury 16
4.2 Depleting of TREM-1 in mice ameliorated the renal pathology after UUO 17
4.3 The role of TREM-1 in M1 vs. M2 Polarized Inflammation 18
4.4 UUO-injured kidney contains a unidentified TREM-1 ligand(s) that could trigger BMDM differentiation into M1 cells 20
4.5 Administration of neutralizing antibodies for GM-CSF and IFN-g inhibited BMDM polarized to the M1 state 22
4.6 TREM-1–expressing macrophages are significantly increased in injured kidney specimens from obstructive uropathy patients 23
5 Discussion 25
6 References 29

Table 1 Primer sequences for real-time polymerase chain reaction 36
Table 2 Comprehensive analysis on CKD samples from three distinct groups of patients. 70

Figure 1. Study design of animal experiments. 39
Figure 2. Regulation of TREM family genes expression in WT mice with UUO. 40
Figure 3. The expression of Trem-1 in KO and WT mice after UUO. 43
Figure 4. Interstitial renal inflammatory macrophage infiltration. 45
Figure 5. Effect of the loss of TREM-1 expression on macrophages ameliorated chronic inflammation. 49
Figure 6. Role of TREM-1 in macrophage polarization. Renal sections were stained with polyclonal antibodies against iNOS and Arg-1. 51
Figure 7. Role of TREM-1 in macrophage polarization. 54
Figure 8. Identification of macrophage phenotype. 55
Figure 9. UUO tissue lysates identifies the diversity in transcriptional profiles of WT and TREM-1−/− mice bone marrow derived macrophages. 57
Figure 10. Relative mRNA expression levels of iNOS(M1), Arg-1(M2), TNF-α and IFN-gamma in BMDM of WT and TREM-1-/- with UUO tissue lysates treatment. 58
Figure 11. Upon UUO tissue lysates challenge for comparison of GM-CSF and IFN-g in WT BMDM that involved in the regulation cytokine-induced M1 polarization. 63
Figure 12. TREM-1 expression was significantly increased in interstitial macrophages of patients with complete obstructive uropathy. 66
Figure 13. Demonstration by double immunofluorescence staining that TREM-1 expression was characteristic of the M1 phenotype significantly increased in tubular interstitium of patients with obstructive uropathy. 68
Figure 14. The putative illustrated mechanism of possible TREM-1 ligand-induced M1 macrophage response. 71

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