發炎反應是宿主對抗病原體感染或組織損傷的一種免疫反應，建設性的發炎反應有助於宿主防禦病原體感染或恢復組織穩定狀態。但是，失調的發炎反應也會導致感染性或炎症性的疾病。 Toll樣受體4（TLR4）是脂多醣（LPS）的識別受體，脂多醣是革蘭氏陰性細菌外膜的組成部分，會引起敗血症。典型的NLRP3炎性小體和非典型性caspase-11或人類caspase-4 / caspase-5炎性小體的活化會導致白介素1β，白介素18和細胞凋亡（pyroptosis）相關的損傷相關分子模式（DAMPs）分泌。TAPE（溶酶體中TBK1蛋白的相關蛋白）是一種先天性免疫的調節劑，目前已被發現其與TLR4路徑有關，並可能參與炎症小體路徑的調節。我的論文工作集中在以下幾個研究目標：目的一是進行ex vivo和in vivo分析，以評估TAPE在TLR4路徑中的作用。目標二和目標三是研究TAPE在調節NLRP3和非典型炎症小體中的作用。我的結果表明，缺乏TAPE會削弱TLR4-Trif路徑導致的IRF3蛋白磷酸化，這表明TAPE參與在TLR4-TRIF路徑去影響第一型IFN的產生。而對於NLRP3炎性體研究，TAPE敲除的巨噬細胞實驗顯示，缺乏TAPE的細胞在幾種NLRP3配體（包括ATP，Nigericin和SiO2）刺激後所產生的白介素1β和白介素1α會被削弱。明礬（Alum）誘導腹膜炎模型的實驗還顯示，TAPE對於召集中性粒細胞和產生白介素1β是必需的。此外，我的研究結果還表明，TAPE參與了初代巨噬細胞和哺乳動物細胞中非典型炎性小體活化。我的結果還發現TAPE與caspase11炎性小體會有相互的作用並與調節其寡聚有關。總結來說，這些數據表明，TAPE是參與典型性NLRP3炎性小體和非典型性caspase-11炎性小體活化的一個調節劑。

Inflammation is a host immune response to pathogen infection or tissue damage. Constructive inflammation helps the host to defend pathogen infection or restore tissue homeostasis. However, dysregulated inflammatory responses often lead to infectious or inflammatory diseases. Toll-like receptor 4 (TLR4) is a pattern-recognition receptor for lipopolysaccharide (LPS), which is a component of the outer membrane of Gram-negative bacteria responsible for sepsis. Canonical NLRP3 inflammasome and non-canonical caspase-11 or human caspase-4/caspase-5 inflammasomes are implicated in inflammatory responses through regulating the secretion of IL-1β, and IL-18, or DAMPs by pyroptosis. TAPE (TBK1-Associated Protein in Endolysosomes) is an innate immune regulator shown to implicate in the TLR4 pathway and potentially in the regulation of the inflammasome pathways. My thesis work focuses on the following study aims. The Aim 1 is to conduct ex vivo and in vivo analyses to assess the role of TAPE in the TLR4 pathway. The Aim 2 and Aim 3 are to study the roles of TAPE in regulating NLRP3 and non-canonical inflammasomes. My results showed that TAPE deficiency impaired the TLR4-Trif pathway to the phosphorylation of IRF3, suggesting that TAPE is involved in the TLR4-TRIF pathway to type I IFN production. For the NLRP3 inflammasome study, TAPE-knockout macrophages were shown to impair the production of IL-1β and IL-1α in response to several NLRP3 ligands, including ATP, Nigericin, and SiO2. In vivo data from the Alum-induced peritonitis model also showed that TAPE was required for the recruitment of neutrophils and IL-1β production. Moreover, my results that TAPE was involved in non-canonical inflammasome activation in primary macrophages and mammalian cells. My results also showed that TAPE was associated with the caspase11 inflammasome and modulated caspase-11 oligomerization. Together, these data suggest that TAPE is a common regulator involved in the activation of canonical NLRP3 inflammasome and non-canonical caspase-11 inflammasome.

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