免疫系統會藉由啟動發炎反應用以清除外來入侵的病原菌，以及協助維持身體的恆定性。然而，過度的發炎反應則會造成發炎性疾病，進而對宿主造成危害。其中，敗血性休克症為宿主受到細菌染後，引發廣泛且不能控制的全身性發炎反應。先天免疫系統主要藉由Pattern recognition receptors (PRRs)來辨識外來病原體具高度保留的Pathogen-associated molecular pattern (PAMPs)，並有效的引起發炎反應。其中， 細胞中的NLRP3、ASC和pro-caspase-1會相互連接組成NLRP3發炎小體，在偵測到細胞質中入侵的病原菌或接受死亡訊息分子時，會切割caspase-1，促使發炎激素IL-1β和IL-18釋放到細胞外造成發炎反應；而活化的caspase-1也會促使細胞進行快速的計畫性死亡，稱為pyroptosis，使細胞脹破而釋放發炎激素和外來病原菌，用以吸引更多免疫細胞前來共同清除病原菌。此外巨噬細胞自身會藉由吞噬作用及自噬作用來清除病原菌。受到病毒感染時，TBK1會協助訊息傳遞進而引起第一型干擾素等抗病毒的先天免疫反應；最近研究指出，TBK1也會參與在細胞自噬小體的形成，對於清除胞內病原菌扮演重要的角色。我們實驗室之前的研究已經發現一個新的先天免疫調控分子，TAPE (TBK1-Associated Protein in Endolysosomes)會影響TLR3、TLR4及RIG-I-like receptors (RLRs)訊息傳遞。由於已知TLR4是細菌內毒素(LPS)的主要受體，所以我們想要進一步研究，TAPE在內毒素所引起的敗血症以及在細菌感染時的角色為何。實驗結果顯示，TAPE基因缺失的小鼠相較於正常小鼠對於內毒素所引起的敗血症具有抵抗性，並且也發現小鼠體中IL-1α的量較低。這顯示了TAPE可能參與在發炎小體的活化路徑中。首先，利用巨噬細胞給予NLRP3發炎小體的活化刺激下，TAPE的缺失確實能有效的抑制NLRP3發炎小體活化所造成IL-β及IL-1α的釋放。在進一步利用免疫沉澱的實驗中，則發現TAPE會和NLRP3形成複合體。此外我們也發現TAPE缺失的巨噬細胞在給予沙門氏桿菌感染後，無法有效活化發炎激素。有趣的是，我們的實驗結果顯示TAPE可以協助細胞自噬作用清除入侵的沙門氏桿菌。另一方面，TAPE也會結合NOD2，正向調控NOD2活化NF-κB啟動子的活性。最後，在小鼠活體實驗中發現TAPE基因缺失小鼠較正常小鼠容易死於沙門氏桿菌的感染，顯示TAPE在活體內抵抗細菌感染的重要性。總結以上實驗結果，無論是在活體外細胞或活體實驗上，皆證實了TAPE在調控發炎反應、敗血症以及對抗細菌免疫機制的重要性。

Inflammation functions to alarm the host immune system to defend against pathogen invasion or to sustain tissue homeostasis. By contrast, deregulation of inflammation often damages the host by causing infectious or inflammatory diseases. For instance, sepsis/septic shock, a deregulated-inflammation state resulting from the systemic bacterial infection, is detrimental to the host. Pattern-recognition receptors (PRRs) function to trigger inflammation upon detecting microbial components. Among these PRRs, Nod-like receptors (NLRs) constitute a family of intracellular receptors that recognize cytoplasmic PAMPs and danger-associated molecular patterns (DAMPs). NLRP3 is a cytosolic NLR acting to detect various PAMPs and DAMPs to mediate inflammasome activation causing the secretion of pro-inflammatory cytokines, like interleukin-1β (IL-1β) and IL-18, and leading to inflammatory cell death called pyroptosis. In addition to inflammation, the cell-autonomous defense mechanisms, like phagocytosis and autophagy, also play key roles in antibacterial innate immunity. TBK1 is an IKK-related kinase shown to regulate type I IFN induction during virus infection and to regulate autophagy during intracellular bacterial infection. TAPE (TBK1-Associated Protein in Endolysosomes) is a recently identified innate immune regulator implicated in the TLR3, TLR4 and cytosolic RIG-like receptors (RLRs) pathways. Here our work aims to assess the potential role of TAPE in regulating innate immune responses during LPS-induced septic shock and bacterial infection. In this study, we showed that TAPE conditional knockout mice were more resistant to LPS-induced septic shock than wild-type littermates, and were impaired in the production of IL-1α. It suggests that TAPE might link the inflammasome activation to the production of IL-1β and IL-1α. Consistently, ex vivo studies showed that TAPE-deficient macrophages were significantly impaired in IL-1β and IL-1α secretion in response to NLRP3 inducers including ATP and nigericin. Moreover, TAPE was shown to form a complex with NLRP3. Of interest, TAPE-deficient macrophages were also impaired in inflammatory cytokine production upon live S. Typhimurium but not E. coli infection. Furthermore, our results from bacterial load analyses revealed that TAPE-deficient macrophages were defective in restricting live S. Typhimurium but not E.coli infection compared to wild type macrophages. Biochemical analyses showed that the cleavage of an autophagy marker LC3 was impaired in TAPE-deficient macrophages, suggesting that TAPE plays a role in autophagic defense against S. Typhimurium. In addition, TAPE was also shown to bind to cytosolic NOD2, and positively regulated NOD2-mediated NF-κB activation upon S. Typhimurium infection or NOD2 ligand MDP stimulation. Finally, TAPE conditional knockout exhibited a lower survival rate upon S. Typhimurium infection, indicating the in vivo importance of TAPE in antibacterial immunity. Collectively, our findings demonstrate the importance of TAPE in regulating inflammation, sepsis and Gram-negative bacterial infection.

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