痛風，為一種常見的代謝性關節炎，由於病患長期罹患高尿酸血症，而尿酸與血液中的鈉離子會形成尿酸結晶，尿酸結晶堆積在四肢關節處所引發的發炎反應。當關節處的尿酸結晶被巨噬細胞辨別到，會誘發巨噬細胞將其吞噬，而其中會活化巨噬細胞內免疫小體inflammasome NLRP3，procaspase-1，釋放出發炎因子IL-1 beta。IL-1 beta是主要參與在尿酸結晶誘導發炎的發炎因子，但尿酸結晶如何去誘導發炎反應的詳細機制仍不明確。Eps8 是一個致癌蛋白，調控Src及Fak的活性，此外Eps8也參與了調控LPS/TLR4 訊息傳遞及誘導巨噬細胞吞噬作用。本研究在探討Eps8 在尿酸結晶所活化procaspase-1路徑所扮演的角色，我們發現在用尿酸結晶刺激人類巨噬細胞THP-1後，Eps8 和其互動蛋白IRSp53，Src 都會有上升的現象。當我們在THP-1中抑制Eps8的表現，隨後其對尿酸結晶刺激所誘導的procaspase-1活化也會跟著下降。我們利用LPS跟IL-1 beta誘導THP-1免疫活化及刺激IL-1 beta/NFkB路徑回饋調控，我們發現Eps8參與尿酸結晶所誘導procaspase-1活化的路徑當中。在mRNA的方面，抑制Eps8表現也會使尿酸結晶誘導procaspase-1及IL-1 beta基因表現有下降的趨勢。綜合以上結果，Src 的活化參與在活化inflammasome NFkB路徑的上游，並且對於Eps8-IRSp53蛋白互動中是必要的存在，而Eps8在尿酸結晶誘導procaspase-1 中活化扮演重要的角色。

Gouty arthritis is a metabolic disease due to hyperuricemia and accumulation of monosodium urate (MSU) crystals in the articular joints and subsequent induction of acute inflammatory response. When MSU crystals are detected and phagocytosis by macrophages, these will induce the activation of inflammasome NLRP3 and procaspase-1, releasing IL-1 beta. IL-1 beta is a major effector cytokine and plays a crucial role in MSU-induced inflammation, but the detail mechanism of MSU-mediated inflammation is not fully elucidated. EGF receptor pathway substrate no.8 (Eps8) is an oncoprotein, regulating the activity of Src and FAK. In addition, Eps8 participates in LPS/TLR4 signaling and regulates LPS-induced phagocytosis in macrophages. In this study, we aim to investigate the role of Eps8 in MSU-induced procaspase-1 activation. We found that Eps8 and its interacting proteins IRSp53 and Src are induced by MSU-treated human macrophage cell line THP-1. When knockdown Eps8, it impairs the expression of procaspase-1 as well as the cleavage of the latter protein in response to MSU treatment. THP-1 were treated with LPS or IL-1 beta to prime THP-1 or form IL-1 beta NFkB signaling feedback loop, we proved that Eps8 is involved in MSU-induced prcocaspase-1 signaling pathway. In mRNA level, silencing Eps8 also affects MSU-induced procaspase-1 activation and IL-1 beta expression. Knockdown Eps8 by lentivirus infection did not reveal the impairment of phagocytosis in THP-1 cells. Given that Src activation is in the upstream of NF-kB that participates in the activation of inflammasome and is required for the Eps8-IRSp53 interaction. Eps8 might plays a critical role in MSU-induced procaspase-1 activation.

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