類鐸受體所介導的NF-kappaB的激活是響應於助氧化和促炎性刺激的血管內皮細胞的一個主要的先天免疫反義。 我們確定了TIFA [TNFalpha receptor-associated factor（TRAF) interacting protein with a FHA damain]在血管內皮細胞中不但參與引發NLRP3炎症小體的誘導（信號1) 也參與了其活化（信號2)。我們首先發現氧化和炎性壓力如atheroprone流和高脂血症在in vitro及 in vivo實驗中皆能誘發與活化TIFA。接著，對於信號1的起動，固醇調節元件結合蛋白2（SREBP2)此一轉錄因子能上調TIFA的信使RNA表現，藉此誘導NF-kappaB和增強NLRP3炎症小體成員的轉錄。然而對於信號2的活化，我們實驗室發現Akt參與了TIFA Thr9的磷酸化，此磷酸畫的作用使TIFA-TIFA嗜同聚合體形成。 Thr9磷酸依賴性TIFA聚合體能夠促使NLRP3炎症小體的具合與活化，而此聚合作用是透過在活化的內皮細胞中TIFA和caspase-1之間的相互作用所達成的。另外， 當TIFA被過度表達時，我們發現我們發現細胞的自噬作用， 單核細胞的黏附作用，以及細胞焦亡反應皆細胞焦亡反應皆上升了。綜合以上結果，我們發現TIFA是透過誘導與加強NLRP3炎症小體活化之信號1和2的內皮先天免疫反應的關鍵介體。

Toll-like receptor-mediated NF-κB activation is a major innate immune reaction of vascular endothelial cells (ECs) in response to pro-oxidative and pro-inflammatory stimuli. We identified that TIFA [abbreviated from TNFα receptor-associated factor (TRAF)-interacting protein with a forkhead-associated (FHA) domain] is a novel regulator of both priming (Signal 1) and activating (Signal 2) signals of NLRP3 inflammasome in ECs. Oxidative and inflammatory stresses such as atheroprone flow and hyperlipidemia induce and activate TIFA in vitro and in vivo. For the priming of Signal 1, sterol regulatory element-binding protein 2 (SREBP2) transactivates TIFA, which in turn induces NF-κB and augments the transcription of NLRP3 inflammasome components. For the activation of Signal 2, our lab has found that Akt is involved in TIFA Thr9 phosphorylation, which is essential for TIFA-TIFA homophilic oligomerization. Thr9 phosphorylation-dependent TIFA oligomerization facilitates the higher-order assembly of NLRP3 inflammasome, as indicated by the interactions between TIFA and caspase-1 in the activated ECs. Furthermore, we revealed that overexpression of TIFA leads to increased autophagy, monocyte adhesion and pyroptosis, indicationg. Our results suggest that TIFA is a crucial mediator in the endothelial innate immune response by potentiating and amplifying NLRP3 inflammasome via augmenting Signals 1 and 2.

誌謝……………………………………………………………………………………...ii
中文摘要………………………….………………………………………………….....iii
Abstract ………………………………………………………………………...……..iv
Introduction
1. Endothelial dysfunction and cardiovascular diseases………………………..1
2. Atherosclerosis……………………………………………………………………..2
3. Shear stress and atherosclerosis.………………………………………..…......3
4. Endothelium innate immune response.………………………………………...4
5. Oxidative stress and Endothelial dysfunction…………………………….......4
6. NLRP3 inflammasome in atherosclerosis..………………………………….....6
7. Sterol regulatory element-binding protein 2 (SREBP2)…….…………………8
8. FHA domain containing protein.…………….………………… ………………..9
9. TRAF-interacting protein with a FHA domain (TIFA)..………….….………..10
10. Inflammasome and pyroptosis………….…………………………………….11
11. Inflammasome and autophagy………….…………………………………….11
12. Inflammasome and monocyte adhesion. …………………………………...12
Rationale and Hypothesis…………………………………………………………..14
Results
1. Oxidative stress induces TIFA in vitro and in vivo..…………………...…….15
2. SREBP2 transactivates TIFA in ECs.…………………………………………..25
3. TIFA is involved in Signal 1 of NLRP3 inflammasome……………………....36
4. TIFA induces the assembly and activation of NLRP3 inflammasome via Signal 2...41
5. TIFA activation induces pyroptosis..………….……………………………….50
6. SREBP2 and TIFA activation are involved in endothelial cell autophagy...53
7. TIFA induces monocyte adhesion to ECs……..……..……………………….57
Materials & Methods
1. Antibodies and reagents………………………………………………………...59
2. Cell line and cell culture ……………………………………………………......59
3. Shear stress experiments…………………………………………………........60
4. RNAi inhibition and adenovirus infection…………………………………......60
5. Binding site prediction and ChIP assay………………………………….…...61
6. Immunoblotting…………………………………………………………….….....61
7. RNA purification and Quantitative RT-PCR (qRT-PCR) …………………….62
8. Animal experiments………………………………………………………..…….62
9. Inflammasome reconstitution assay…………………………………….….….63
10. Immunoprecipitation.………………………………………………………......63
11. Flow cytometry detection of pyroptotic cells..……………………...……...63
12. Monocyte adhesion assay………………………………………………...…..64
13. Statistical analysis……………………………………………………….….….64
Discussion……………………………………..…………………………….……….65
References………………………………………………………………….………..73
Graphic summary…………..……………………………………89
Tables…………..……………………………………………90

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