臺灣博碩士論文加值系統

在腸道表皮細胞中，IL-22引起之STAT3磷酸化(pSTAT3)可維持腸道免疫平衡。許多參與IL-22-pSTAT3訊息傳遞的基因已經被定義為腸道發炎疾病之危險因子，而其中部分基因已被應用於治療標的。若能發現更多關於IL-22-pSTAT3訊息傳遞的基因將有助於臨床病人的治療。我們的研究顯示activating transcription factor 3 (ATF3)參與調控IL-22-pSTAT3訊息傳遞以維持腸道穩定。相對於野生型(WT)小鼠，ATF3基因剔除導致小鼠的囊狀小體減少和大腸長度縮短。在DSS引起的腸道發炎模式中，DSS會造成ATF3基因剔除小鼠嚴重的腸道發炎，而發炎可經由注入WT小鼠的腸道表皮類器官細胞得到減緩。IL-22-pSTAT3訊息傳遞在腸道表皮幹細胞及潘氏細胞維持腸道再生及宿主與微生物的交互作用扮演重要地角色。我們的研究發現ATF3基因剃除不但導致腸道幹細胞生長與再生受損，而且也使得潘氏細胞分泌的抗菌胜肽(Anti-microbial peptide, AMP)減少。在機制方面，我們發現IL-22正向調控ATF3的表現以使得STAT3磷酸化和抗菌胜肽的生成。有趣的是ATF3並不會直接作用在STAT3上，而是藉由抑制兩種酪氨酸磷酸酶SHP2和PTP-Meg2使得STAT3磷酸化。我們更近一步地發現ATF3參與IL-6引起T細胞的STAT3活化和Th17細胞產生IL-22和IL-17A的數量。綜合以上結果，我們推論ATF3經由調控腸道表皮細胞中的IL-22-pSTAT3訊息傳遞和Th17細胞的IL-6-pSTAT3訊息傳遞以維持腸道黏膜免疫的平衡。

English Abstract
In gut epithelium, IL-22 transmits signals through STAT3 phosphorylation (pSTAT3) which provides intestinal immunity. Many components in the IL-22-pSTAT3 pathway have been identified as risk factors for inflammatory bowel disease (IBD) and some of them are considered as promising therapeutic targets. However, new perspectives are still needed to understand IL-22-pSTAT3 signaling for effective clinical interventions in IBD patients. Here, we revealed activating transcription factor 3 (ATF3), recently identified to be upregulated in patients with active IBD, as a crucial player in the epithelial IL-22-pSTAT3 signaling cascade. We found ATF3 is central to intestinal homeostasis and provides protection during colitis. Loss of ATF3 led to decreased crypt numbers, more shortened colon length, impaired ileal fucosylation at the steady state, and lethal disease activity during DSS-induced colitis which can be effectively ameliorated by rectal transplantation of wild-type colonic organoids. Epithelial stem cells and Paneth cells form a niche to orchestrate epithelial regeneration and host-microbe interactions, and IL-22-pSTAT3 signaling is a key guardian for this niche. We found ATF3 is critical for niche maintenance as ATF3 deficiency caused compromised stem cell growth and regeneration, as well as Paneth cell degeneration and loss of anti-microbial peptide (AMP)-producing granules, indicative of malfunction of Paneth/stem cell network. Mechanistically, we found IL-22 upregulates ATF3, which is required to relay IL-22 signaling leading to STAT3 phosphorylation and subsequent AMP induction. Intriguingly, ATF3 itself does not act on STAT3 directly, instead ATF3 regulates pSTAT3 by negatively targeting protein tyrosine phosphatases (PTPs) including SHP2 and PTP-Meg2. Furthermore, we identified ATF3 is also involved in IL-6-mediated STAT3 activation in T cells and loss of ATF3 leads to reduced capacity of Th17 cells to produce their signature cytokine IL-22 and IL-17A. Collectively, our results suggest that via IL-22-pSTAT3 signaling in the epithelium and IL-6-pSTAT3 signaling in Th17 cells, ATF3 mediates a cross-regulation in the barrier to maintain mucosal homeostasis and immunity.

CONTENTS i
Acknowledgment iv
Abstract vi
Abbreviations 1
1.Introduction 3
Introductory figure. 4
1.1 Role of intestinal mucosal barrier in IBD immuno-pathogenesis. 5
1.2 Role of IL-22 in mucosal immunity in health and disease. 8
1.3 STAT3 in intestinal immunity and its Regulators 11
1.4 ATF3 and its connection to intestinal mucosal immunity 16
1.5 Conclusion 19
2.Results and figures 20
2.1 ATF3 is the platform for balancing homeostais in both ileum and colon 21
2.2 ATF3 is required for restitution process in IECs 29
2.3 Disruption of Paneth cell homeostasis in ATF3-/- mice 30
2.4 Epithelial ATF3 is protective against DSS-induced colitis 33
2.5 Rectal organoid transfer into DSS treated ATF3-/- mice ameliorates colitis 39
2.6 ATF3 is a downstream target of IL-22 and required for IL-22 induced AMPs 43
2.7 impaired IL-22 induction of STAT3 phosphorylation in ATF3-deficient epithelial cells. 49
2.8 ATF3 protects IL-22 induced pSTAT3 via targeting phosphatases 52
2.9 ATF3 is required for intestinal Th17 cell functionality 57
3.Discussion 65
4.Future directions 77
5.Materaila and methods 81
5.1 Mice 82
5.2 DSS induced colitis. 82
5.3 Endoscopic view of colon after DSS intake 83
5.4 Histopathological sections preparation 84
5.5 Histomorphological evaluation 85
5.6 Citrobacter rodentium oral infection 85
5.7 Isolation of intestinal epithelial cells 86
5.8 Flow cytometry analysis of intestinal epithelial cells 87
5.9 Immunofluorescence staining of intestinal tissue sections 88
5.10 Apoptosis detection assay by TUNEL 89
5.11 Preparation of wholemount ileum tissue sections for three dimensional images 90
5.12.Intestinal organoid culture 91
5.13 Intrarectal organoid transplantation after DSS intake 93
5.14 Intracellular organoid staining of pSTAT3 94
5.15 Generation of ATF3-deficient CMT-93 cells by CRISPR-Cas9 95
5.16 Silencing the mouse Ptpn11(SHP2) gene expression in CMT-93 96
5.17 In-vitro wound healing assay 97
5.18 In-vitro cell proliferation assay 98
5.19 Isolation, culture, and stimulation of intestinal lamina propria cells 98
5.20 RNA extraction and quantitative real-time PCR analysis 101
5.20 Western Blot analysis 101
5.21 Electrophoretic Mobility Shift Assay (EMSA) 103
5.22 Chromatin Immunoprecipitation (ChIP) 104
5.23 Transmission Electron Microscopy 106
5.24 Statistical analysis 107
6.Tables 108
6.1 Table 1 (List of antibodeis used in this study) 109
6.2 Table 2 (List of Reagents used in this study) 111
6.3 Table 3 (List of primers) 114
7.Ethics statemnet 116
8.Funding 116
9.Acknowledgement 116

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