NKT細胞在脂肪組織代謝性炎癥中的功能研究
發(fā)布時間：2019-07-08 12:36
【摘要】：隨著生活水平的提高,肥胖已成為人類健康的重要威脅因素之一。肥胖可以引起胰島素抵抗,進而導(dǎo)致動脈粥樣硬化、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為代謝性炎癥。至今為止,代謝性炎癥觸發(fā)機制仍不清楚。研究發(fā)現(xiàn),免疫系統(tǒng)穩(wěn)態(tài)的破壞對于代謝性炎癥的發(fā)生發(fā)展起到關(guān)鍵作用。巨噬細胞、NK細胞、ILC2細胞和NKT細胞等多種免疫細胞都參與了肥胖引起的代謝性炎癥。其中巨噬細胞的功能研究的最多,正常狀態(tài)下脂肪組織巨噬細胞以抑炎的M2型巨噬細胞為主,但是隨著肥胖和炎癥的發(fā)展,脂肪組織中促炎的M1型巨噬細胞增加而M2型巨噬細胞減少。M1巨噬細胞產(chǎn)生大量的促炎型細胞因子會促進脂肪組織功能失調(diào)進而導(dǎo)致代謝性炎癥和胰島素抵抗。但是,導(dǎo)致M1和M2巨噬細胞比例失衡的因素還不是很清楚。和傳統(tǒng)T細胞不同,NKT細胞不能識別MHC分子提呈的蛋白類抗原而是識別由CD1d分子提呈的脂類抗原。NKT細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,不同研究組對于NKT細胞在代謝性炎癥中的功能還存在較大的爭議。NKT細胞與M1、M2巨噬細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巨噬細胞的CD1d表達特異性下降而M1巨噬細胞的CD1d表達沒有變化。M2巨噬細胞表面CD1d表達的下調(diào)影響了 M2巨噬細胞的抗原提呈能力,進而導(dǎo)致M1巨噬細胞成為NKT細胞的主要抗原提呈細胞。分選M1或M2巨噬細胞與NKT細胞共培養(yǎng),與M1巨噬細胞相比,M2巨噬細胞活化NKT細胞后,NKT細胞產(chǎn)生更多的IL4和IL13,而IFNγ分泌相對較少。上述結(jié)果說明,M1型巨噬細胞與M2型巨噬細胞活化NKT細胞后會引起不同的免疫應(yīng)答。進一步,利用M2巨噬細胞CD1d缺陷小鼠,Lyz2cre Cd1dfl/fl,Lyz2△/△)和M1巨噬細胞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照鼠更為嚴重,并且該現(xiàn)象一直持續(xù)到16周,而到20周后就和對照鼠接近。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。這說明不同巨噬細胞與NKT細胞相互作用改變了 NKT細胞的血糖調(diào)控能力。同時,在CD1d條件性敲除鼠中我們也發(fā)現(xiàn),脂肪組織M2巨噬細胞活化NKT細胞會促進Th2型免疫反應(yīng),促進M2巨噬細胞極化進而抑制代謝性炎癥和胰島素抵抗。相反,脂肪組織M1巨噬細胞活化NKT細胞會促進Th1型免疫反應(yīng),抑制M2巨噬細胞極化進而促進代謝性炎癥和胰島素抵抗。綜上所述,我們的結(jié)果說明肥胖小鼠脂肪組織M2巨噬細胞CD1d的特異性下降作為起始代謝性炎癥的信號之一,改變了 NKT細胞的免疫功能進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】：中國科學(xué)技術(shù)大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2017
【分類號】：R589.2
本文編號：2511589
[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】：中國科學(xué)技術(shù)大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2017
【分類號】：R589.2
【參考文獻】
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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