發(fā)布時(shí)間：2019-07-08 12:36

【摘要】：隨著生活水平的提高,肥胖已成為人類(lèi)健康的重要威脅因素之一。肥胖可以引起胰島素抵抗,進(jìn)而導(dǎo)致動(dòng)脈粥樣硬化、高血壓和2型糖尿病等疾病。肥胖往往伴隨著機(jī)體多種組織,例如脂肪組織、肝臟、胰腺等組織的慢性炎癥。這種由肥胖引起的慢性炎癥也被稱(chēng)為代謝性炎癥。至今為止,代謝性炎癥觸發(fā)機(jī)制仍不清楚。研究發(fā)現(xiàn),免疫系統(tǒng)穩(wěn)態(tài)的破壞對(duì)于代謝性炎癥的發(fā)生發(fā)展起到關(guān)鍵作用。巨噬細(xì)胞、NK細(xì)胞、ILC2細(xì)胞和NKT細(xì)胞等多種免疫細(xì)胞都參與了肥胖引起的代謝性炎癥。其中巨噬細(xì)胞的功能研究的最多,正常狀態(tài)下脂肪組織巨噬細(xì)胞以抑炎的M2型巨噬細(xì)胞為主,但是隨著肥胖和炎癥的發(fā)展,脂肪組織中促炎的M1型巨噬細(xì)胞增加而M2型巨噬細(xì)胞減少。M1巨噬細(xì)胞產(chǎn)生大量的促炎型細(xì)胞因子會(huì)促進(jìn)脂肪組織功能失調(diào)進(jìn)而導(dǎo)致代謝性炎癥和胰島素抵抗。但是,導(dǎo)致M1和M2巨噬細(xì)胞比例失衡的因素還不是很清楚。和傳統(tǒng)T細(xì)胞不同,NKT細(xì)胞不能識(shí)別MHC分子提呈的蛋白類(lèi)抗原而是識(shí)別由CD1d分子提呈的脂類(lèi)抗原。NKT細(xì)胞具有重要的免疫調(diào)節(jié)能力,在代謝性炎癥中也起到重要的調(diào)控作用。但是,不同研究組對(duì)于NKT細(xì)胞在代謝性炎癥中的功能還存在較大的爭(zhēng)議。NKT細(xì)胞與M1、M2巨噬細(xì)胞比例失衡以及代謝性炎癥的關(guān)系仍不清楚。我們發(fā)現(xiàn),隨著肥胖的發(fā)展,在代謝性炎癥發(fā)生前,小鼠脂肪組織M2巨噬細(xì)胞的CD1d表達(dá)特異性下降而M1巨噬細(xì)胞的CD1d表達(dá)沒(méi)有變化。M2巨噬細(xì)胞表面CD1d表達(dá)的下調(diào)影響了 M2巨噬細(xì)胞的抗原提呈能力,進(jìn)而導(dǎo)致M1巨噬細(xì)胞成為NKT細(xì)胞的主要抗原提呈細(xì)胞。分選M1或M2巨噬細(xì)胞與NKT細(xì)胞共培養(yǎng),與M1巨噬細(xì)胞相比,M2巨噬細(xì)胞活化NKT細(xì)胞后,NKT細(xì)胞產(chǎn)生更多的IL4和IL13,而IFNγ分泌相對(duì)較少。上述結(jié)果說(shuō)明,M1型巨噬細(xì)胞與M2型巨噬細(xì)胞活化NKT細(xì)胞后會(huì)引起不同的免疫應(yīng)答。進(jìn)一步,利用M2巨噬細(xì)胞CD1d缺陷小鼠,Lyz2cre Cd1dfl/fl,Lyz2△/△)和M1巨噬細(xì)胞CD1d缺陷小鼠(Cd11cre Cd1dfl/fl,Cd11c△/△)我們發(fā)現(xiàn),喂高脂飼料8周后Lyz2△/△小鼠血糖不耐受較對(duì)照鼠更為嚴(yán)重,并且該現(xiàn)象一直持續(xù)到16周,而到20周后就和對(duì)照鼠接近。相反,Cd11c△/△小鼠到16周才看到血糖不耐受明顯改善,并且持續(xù)到20周以上。這說(shuō)明不同巨噬細(xì)胞與NKT細(xì)胞相互作用改變了 NKT細(xì)胞的血糖調(diào)控能力。同時(shí),在CD1d條件性敲除鼠中我們也發(fā)現(xiàn),脂肪組織M2巨噬細(xì)胞活化NKT細(xì)胞會(huì)促進(jìn)Th2型免疫反應(yīng),促進(jìn)M2巨噬細(xì)胞極化進(jìn)而抑制代謝性炎癥和胰島素抵抗。相反,脂肪組織M1巨噬細(xì)胞活化NKT細(xì)胞會(huì)促進(jìn)Th1型免疫反應(yīng),抑制M2巨噬細(xì)胞極化進(jìn)而促進(jìn)代謝性炎癥和胰島素抵抗。綜上所述,我們的結(jié)果說(shuō)明肥胖小鼠脂肪組織M2巨噬細(xì)胞CD1d的特異性下降作為起始代謝性炎癥的信號(hào)之一,改變了 NKT細(xì)胞的免疫功能進(jìn)而打破了脂肪組織免疫穩(wěn)態(tài)的平衡。
[Abstract]:With the improvement of living standards, obesity has become one of the important threats to human health. Obesity can cause insulin resistance, which in turn leads to atherosclerosis, hypertension and type 2 diabetes. Obesity is often accompanied by chronic inflammation of a variety of tissues, such as adipose tissue, liver, pancreas and so on. This chronic inflammation caused by obesity is also known as metabolic inflammation. So far, the trigger mechanism of metabolic inflammation is still unclear. It has been found that the destruction of immune system homeostasis plays a key role in the occurrence and development of metabolic inflammation. Many immune cells, such as macrophages, NK cells, ILC2 cells and NKT cells, are involved in metabolic inflammation caused by obesity. Among them, the function of macrophages is the most studied. Under normal conditions, the macrophages of adipose tissue are mainly M2 type macrophages, but with the development of obesity and inflammation, the number of inflammatory macrophage M1 type macrophages in adipose tissue increases and M2 type macrophages decrease. M1 macrophages produce a large number of pro-inflammatory cytokines that promote adipose tissue dysfunction and lead to metabolic inflammation and insulin resistance. However, the factors leading to the imbalance of M 1 and M 2 macrophages are not very clear. Different from the traditional T cells, NKT cells can not recognize the protein antigens presented by MHC molecules, but recognize the lipid antigens submitted by CD1d molecules. NKT cells have important immunomodulatory ability and also play an important regulatory role in metabolic inflammation. However, the function of NKT cells in metabolic inflammation is still controversial in different research groups. The relationship between NKT cells and M1, M2 macrophage ratio imbalance and metabolic inflammation is still unclear. We found that with the development of obesity, the specific expression of CD1d in M2 macrophages of mouse adipose tissue decreased while the CD1d expression of M1 macrophages did not change with the development of obesity. The down-regulation of CD1d expression on M2 macrophages affected the antigen presentation ability of M2 macrophages, which led M1 macrophages to become the main antigen presenting cells of NKT cells. M1 or M2 macrophages were co-cultured with NKT cells. Compared with M1 macrophages, when M2 macrophages activated NKT cells, NKT cells produced more IL4 and IL13, while IFN gamma secretion was relatively less. These results suggest that the activation of NKT cells by M1 macrophages and M2 macrophages can induce different immune responses. Furthermore, using M2 macrophage CD1d deficient mice (Lyz2cre Cd1dfl/fl,Lyz2 /) and M1 macrophage CD1d deficient mice (Cd11cre Cd1dfl/fl,Cd11c /), we found that the blood glucose tolerance of Lyz2 / mice was more serious than that of control mice after 8 weeks of feeding high fat diet, and the phenomenon lasted until 16 weeks, but was close to that of the control mice after 20 weeks. On the contrary, Cd11c / mice did not see a significant improvement in blood glucose tolerance until 16 weeks and lasted for more than 20 weeks. This suggests that the interaction between different macrophages and NKT cells changes the ability of NKT cells to regulate blood glucose. At the same time, we also found that the activation of NKT cells by M2 macrophages in adipose tissue promoted Th2 type immune response, promoted M2 macrophage polarization and inhibited metabolic inflammation and insulin resistance in CD1d conditioned knockout mice. On the contrary, the activation of NKT cells by M1 macrophages in adipose tissue can promote Th1 type immune response, inhibit the polarization of M2 macrophages and promote metabolic inflammation and insulin resistance. In conclusion, our results suggest that the specific decrease of CD1d in adipose tissue M2 macrophages of obese mice is one of the signals of initial metabolic inflammation, which changes the immune function of NKT cells and breaks the balance of immune homeostasis of adipose tissue.
【學(xué)位授予單位】：中國(guó)科學(xué)技術(shù)大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類(lèi)號(hào)】：R589.2

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相關(guān)期刊論文 前1條

1 Ivana Mikolasevic;Sandra Milic;Tamara Turk Wensveen;Ivana Grgic;Ivan Jakopcic;Davor Stimac;Felix Wensveen;Lidija Orlic;;Nonalcoholic fatty liver disease-A multisystem disease?[J];World Journal of Gastroenterology;2016年43期

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本文編號(hào)：2511589