RIP3介導(dǎo)的細(xì)胞壞死通路在心血管慢性免疫疾病上的關(guān)鍵作用
發(fā)布時(shí)間：2018-07-28 14:30
【摘要】：冠心病的發(fā)生是一個(gè)世界性的致死率很高的疾病,也是一種慢性炎癥疾病,炎癥在疾病的發(fā)生中起到了很重要的推動(dòng)作用。其中動(dòng)脈粥樣硬化是一個(gè)現(xiàn)代社會(huì)主要的致人類(lèi)死亡的疾病。由于脂代謝障礙造成的血液中氧化型低密度脂蛋白(oxLDL)水平升高是形成動(dòng)脈粥樣硬化的主要原因。但是炎癥反應(yīng)是如何在疾病中起推動(dòng)疾病進(jìn)程的作用還并不十分清楚。在最新的研究中,本實(shí)驗(yàn)室報(bào)道了RIP3磷酸化是誘導(dǎo)細(xì)胞程序性壞死途徑的關(guān)鍵調(diào)控蛋白。ApoE基因敲除(ApoE-/-)的小鼠是一種經(jīng)典的動(dòng)脈粥樣硬化疾病模型,會(huì)在主動(dòng)脈瓣膜和主動(dòng)脈內(nèi)壁形成斑塊,堵塞血管。我們使用我們研發(fā)的RIP3磷酸化抗體來(lái)檢測(cè)ApoE-/-小鼠動(dòng)脈粥樣硬化斑塊,發(fā)現(xiàn)在動(dòng)脈粥樣硬化斑塊的壞死腔中有磷酸化的RIP3的表達(dá)。并且,我們從動(dòng)脈粥樣硬化斑塊中提取mRNA,檢測(cè)其中的mRNA表達(dá)水平,篩選出10個(gè)炎癥因子,包括IL-1α,在RIP3-/-ApoE-/-小鼠斑塊中表達(dá)水平明顯低于RIP3+/+ApoE-/-小鼠。RIP3+/+ApoE-/-小鼠體內(nèi)的脂肪組織的淋巴細(xì)胞滲透和皮膚組織的損傷顯著高于RIP3-/-ApoE-/-小鼠。Ly6chi單核細(xì)胞的百分?jǐn)?shù)在RIP3+/+ApoE-/-動(dòng)脈粥樣硬化小鼠血液中隨著病情加劇會(huì)逐漸升高。Ly6chi單核細(xì)胞的百分?jǐn)?shù)在RIP3+/+ApoE-/-小鼠血液中顯著高于RIP3-/-ApoE-/-小鼠。血液中的不斷從骨髓中產(chǎn)生的免疫細(xì)胞會(huì)招募到動(dòng)脈粥樣硬化的斑塊,來(lái)吞噬oxLDL形成泡沫細(xì)胞,巨噬細(xì)胞死亡會(huì)形成斑塊,并發(fā)出死亡損傷相關(guān)的分子信號(hào)來(lái)吸引和招募更多的免疫細(xì)胞來(lái)到斑塊,這個(gè)惡性循環(huán)不斷的重復(fù)從而加劇著疾病的進(jìn)程。但是我們發(fā)現(xiàn)在動(dòng)脈粥樣硬化疾病的發(fā)生中很重要的一點(diǎn)是RIP3-/-ApoE-/-小鼠的壽命遠(yuǎn)遠(yuǎn)長(zhǎng)于RIP3+/+ApoE-/-小鼠。并且我們發(fā)現(xiàn)了RIP3磷酸化介導(dǎo)的細(xì)胞壞死是發(fā)生炎癥和病理?yè)p傷的起因,起到了關(guān)鍵的引起小鼠死亡的作用,是擴(kuò)大炎癥損傷的關(guān)鍵點(diǎn)。因此,從抑制RIP3磷酸化介導(dǎo)的細(xì)胞壞死到在動(dòng)脈粥樣硬化疾病中延長(zhǎng)REP3-/-ApoE-/-小鼠的壽命,可見(jiàn)RIP3在調(diào)控細(xì)胞壞死中的重要作用。所以,我們發(fā)現(xiàn)了受RIP3磷酸化而引起的細(xì)胞壞死是發(fā)生炎癥和病理?yè)p傷的起因,是招募炎癥因子擴(kuò)大炎癥損傷的關(guān)鍵點(diǎn),起到了關(guān)鍵的引起小鼠死亡的作用。這個(gè)研究提示了RIP3磷酸化介導(dǎo)的程序性細(xì)胞壞死可以引起炎癥反應(yīng)的不斷擴(kuò)大和循環(huán),這是造成動(dòng)脈粥樣硬化過(guò)早死亡的一個(gè)主要原因。RIP3磷酸化而引起的細(xì)胞壞死的作用不僅表現(xiàn)在對(duì)巨噬細(xì)胞的死亡和炎癥因子表達(dá)水平上的改變,也表現(xiàn)在動(dòng)脈粥樣硬化小鼠的多種器官的損傷作用上,正是這種全面的損害加快了動(dòng)脈粥樣硬化小鼠的死亡。因此,細(xì)胞壞死的關(guān)鍵開(kāi)關(guān)RIP3在生物個(gè)體上的介導(dǎo)壞死的作用也得到了證實(shí),并找到了新的RIP3起作用的動(dòng)物疾病模型,打開(kāi)了研究RIP3作用的更廣泛的領(lǐng)域。我們還將繼續(xù)對(duì)RIP3磷酸化而引起的細(xì)胞壞死的功能和通路研究下去,希望能對(duì)促進(jìn)好的藥物的開(kāi)發(fā),治療人類(lèi)的疑難疾病提供一些有益的幫助。
[Abstract]:The occurrence of coronary heart disease is a worldwide disease with high mortality and a chronic inflammatory disease. Inflammation plays an important role in the occurrence of disease. Among them, atherosclerosis is a major human death disease in modern society. The oxidized low density lipoprotein in blood caused by lipid metabolism disorders. Elevated levels of oxLDL are the main cause of atherosclerosis. But the role of the inflammatory response in the disease is not very clear. In the latest study, the laboratory reported that RIP3 phosphorylation is the key regulatory protein.ApoE gene knockout (ApoE-/-) that induces cellular programmed necrosis. Mice are a classic atherosclerotic disease model, forming plaque and blocking vessels on the aortic valve and the inner wall of the aorta. We use the RIP3 phosphorylation antibody we developed to detect atherosclerotic plaques in ApoE-/- mice, and the expression of phosphorylated RIP3 in the necrotic cavity of atherosclerotic plaques. We extract mRNA from atherosclerotic plaques to detect the level of mRNA expression and screen out 10 inflammatory factors, including IL-1 alpha. The expression level in the plaque of RIP3-/-ApoE-/- mice is significantly lower than that of RIP3+/+ApoE-/- mice. The lymphatic cell infiltration and skin tissue damage in the adipose tissue of the RIP3+/+ApoE-/- mice are significantly higher than those of the RIP3-. The percentage of.Ly6chi monocytes in /-ApoE-/- mice was gradually increased in the blood of RIP3+/+ApoE-/- atherosclerotic mice. The percentage of.Ly6chi mononuclear cells was significantly higher in the blood of RIP3+/+ApoE-/- mice than in RIP3-/-ApoE-/- mice. The atherosclerotic plaques that engulf oxLDL form foam cells, the death of macrophages form plaques and emit molecular signals associated with death and injury to attract and recruit more immune cells to the plaque, which is repeated and thus exacerbates the process of disease. But we found the occurrence of atherosclerotic disease. It is important that RIP3-/-ApoE-/- mice live far longer than RIP3+/+ApoE-/- mice. And we have found that RIP3 phosphorylation mediated cell necrosis is the cause of inflammation and pathological damage, which plays a key role in causing death in mice and is the key to enlarging inflammatory damage. Therefore, it is mediated by inhibiting the phosphorylation of RIP3. Cell necrosis to prolong the life of REP3-/-ApoE-/- mice in atherosclerotic diseases can be seen as an important role of RIP3 in regulating cell necrosis. Therefore, we found that the cell necrosis caused by RIP3 phosphorylation is the cause of inflammation and pathological damage, which is the key point to recruit inflammatory factors to enlarge the inflammatory damage. This study suggests that RIP3 phosphorylation mediated programmed cell necrosis can cause the continuous expansion and circulation of inflammatory reactions, which is a major cause of premature death of atherosclerosis, the role of cell necrosis caused by.RIP3 phosphorylation not only in the death of macrophages and in the death of macrophages. The changes in the expression level of inflammatory factors are also manifested in the damage of various organs in the atherosclerotic mice, and it is this comprehensive damage that accelerates the death of atherosclerotic mice. Therefore, the role of the key switch, RIP3, to mediate necrosis in the biological individual is also confirmed, and a new RIP3 is found. The functional animal disease model has opened up a wider field of research on the role of RIP3, and we will continue to study the functions and pathways of cell necrosis caused by the phosphorylation of RIP3, and hope to provide some helpful help to the development of good drugs and the treatment of difficult diseases of human beings.
【學(xué)位授予單位】：中國(guó)農(nóng)業(yè)大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類(lèi)號(hào)】：R54
本文編號(hào)：2150528
[Abstract]:The occurrence of coronary heart disease is a worldwide disease with high mortality and a chronic inflammatory disease. Inflammation plays an important role in the occurrence of disease. Among them, atherosclerosis is a major human death disease in modern society. The oxidized low density lipoprotein in blood caused by lipid metabolism disorders. Elevated levels of oxLDL are the main cause of atherosclerosis. But the role of the inflammatory response in the disease is not very clear. In the latest study, the laboratory reported that RIP3 phosphorylation is the key regulatory protein.ApoE gene knockout (ApoE-/-) that induces cellular programmed necrosis. Mice are a classic atherosclerotic disease model, forming plaque and blocking vessels on the aortic valve and the inner wall of the aorta. We use the RIP3 phosphorylation antibody we developed to detect atherosclerotic plaques in ApoE-/- mice, and the expression of phosphorylated RIP3 in the necrotic cavity of atherosclerotic plaques. We extract mRNA from atherosclerotic plaques to detect the level of mRNA expression and screen out 10 inflammatory factors, including IL-1 alpha. The expression level in the plaque of RIP3-/-ApoE-/- mice is significantly lower than that of RIP3+/+ApoE-/- mice. The lymphatic cell infiltration and skin tissue damage in the adipose tissue of the RIP3+/+ApoE-/- mice are significantly higher than those of the RIP3-. The percentage of.Ly6chi monocytes in /-ApoE-/- mice was gradually increased in the blood of RIP3+/+ApoE-/- atherosclerotic mice. The percentage of.Ly6chi mononuclear cells was significantly higher in the blood of RIP3+/+ApoE-/- mice than in RIP3-/-ApoE-/- mice. The atherosclerotic plaques that engulf oxLDL form foam cells, the death of macrophages form plaques and emit molecular signals associated with death and injury to attract and recruit more immune cells to the plaque, which is repeated and thus exacerbates the process of disease. But we found the occurrence of atherosclerotic disease. It is important that RIP3-/-ApoE-/- mice live far longer than RIP3+/+ApoE-/- mice. And we have found that RIP3 phosphorylation mediated cell necrosis is the cause of inflammation and pathological damage, which plays a key role in causing death in mice and is the key to enlarging inflammatory damage. Therefore, it is mediated by inhibiting the phosphorylation of RIP3. Cell necrosis to prolong the life of REP3-/-ApoE-/- mice in atherosclerotic diseases can be seen as an important role of RIP3 in regulating cell necrosis. Therefore, we found that the cell necrosis caused by RIP3 phosphorylation is the cause of inflammation and pathological damage, which is the key point to recruit inflammatory factors to enlarge the inflammatory damage. This study suggests that RIP3 phosphorylation mediated programmed cell necrosis can cause the continuous expansion and circulation of inflammatory reactions, which is a major cause of premature death of atherosclerosis, the role of cell necrosis caused by.RIP3 phosphorylation not only in the death of macrophages and in the death of macrophages. The changes in the expression level of inflammatory factors are also manifested in the damage of various organs in the atherosclerotic mice, and it is this comprehensive damage that accelerates the death of atherosclerotic mice. Therefore, the role of the key switch, RIP3, to mediate necrosis in the biological individual is also confirmed, and a new RIP3 is found. The functional animal disease model has opened up a wider field of research on the role of RIP3, and we will continue to study the functions and pathways of cell necrosis caused by the phosphorylation of RIP3, and hope to provide some helpful help to the development of good drugs and the treatment of difficult diseases of human beings.
【學(xué)位授予單位】：中國(guó)農(nóng)業(yè)大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類(lèi)號(hào)】：R54
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