NKT细胞在脂肪组织代谢性炎症中的功能研究
发布时间：2019-07-08 12:36
【摘要】：随着生活水平的提高,肥胖已成为人类健康的重要威胁因素之一。肥胖可以引起胰岛素抵抗,进而导致动脉粥样硬化、高血压和2型糖尿病等疾病。肥胖往往伴随着机体多种组织,例如脂肪组织、肝脏、胰腺等组织的慢性炎症。这种由肥胖引起的慢性炎症也被称为代谢性炎症。至今为止,代谢性炎症触发机制仍不清楚。研究发现,免疫系统稳态的破坏对于代谢性炎症的发生发展起到关键作用。巨噬细胞、NK细胞、ILC2细胞和NKT细胞等多种免疫细胞都参与了肥胖引起的代谢性炎症。其中巨噬细胞的功能研究的最多,正常状态下脂肪组织巨噬细胞以抑炎的M2型巨噬细胞为主,但是随着肥胖和炎症的发展,脂肪组织中促炎的M1型巨噬细胞增加而M2型巨噬细胞减少。M1巨噬细胞产生大量的促炎型细胞因子会促进脂肪组织功能失调进而导致代谢性炎症和胰岛素抵抗。但是,导致M1和M2巨噬细胞比例失衡的因素还不是很清楚。和传统T细胞不同,NKT细胞不能识别MHC分子提呈的蛋白类抗原而是识别由CD1d分子提呈的脂类抗原。NKT细胞具有重要的免疫调节能力,在代谢性炎症中也起到重要的调控作用。但是,不同研究组对于NKT细胞在代谢性炎症中的功能还存在较大的争议。NKT细胞与M1、M2巨噬细胞比例失衡以及代谢性炎症的关系仍不清楚。我们发现,随着肥胖的发展,在代谢性炎症发生前,小鼠脂肪组织M2巨噬细胞的CD1d表达特异性下降而M1巨噬细胞的CD1d表达没有变化。M2巨噬细胞表面CD1d表达的下调影响了 M2巨噬细胞的抗原提呈能力,进而导致M1巨噬细胞成为NKT细胞的主要抗原提呈细胞。分选M1或M2巨噬细胞与NKT细胞共培养,与M1巨噬细胞相比,M2巨噬细胞活化NKT细胞后,NKT细胞产生更多的IL4和IL13,而IFNγ分泌相对较少。上述结果说明,M1型巨噬细胞与M2型巨噬细胞活化NKT细胞后会引起不同的免疫应答。进一步,利用M2巨噬细胞CD1d缺陷小鼠,Lyz2cre Cd1dfl/fl,Lyz2△/△)和M1巨噬细胞CD1d缺陷小鼠(Cd11cre Cd1dfl/fl,Cd11c△/△)我们发现,喂高脂饲料8周后Lyz2△/△小鼠血糖不耐受较对照鼠更为严重,并且该现象一直持续到16周,而到20周后就和对照鼠接近。相反,Cd11c△/△小鼠到16周才看到血糖不耐受明显改善,并且持续到20周以上。这说明不同巨噬细胞与NKT细胞相互作用改变了 NKT细胞的血糖调控能力。同时,在CD1d条件性敲除鼠中我们也发现,脂肪组织M2巨噬细胞活化NKT细胞会促进Th2型免疫反应,促进M2巨噬细胞极化进而抑制代谢性炎症和胰岛素抵抗。相反,脂肪组织M1巨噬细胞活化NKT细胞会促进Th1型免疫反应,抑制M2巨噬细胞极化进而促进代谢性炎症和胰岛素抵抗。综上所述,我们的结果说明肥胖小鼠脂肪组织M2巨噬细胞CD1d的特异性下降作为起始代谢性炎症的信号之一,改变了 NKT细胞的免疫功能进而打破了脂肪组织免疫稳态的平衡。
[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.
【学位授予单位】：中国科学技术大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R589.2
本文编号：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.
【学位授予单位】：中国科学技术大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R589.2
【参考文献】
相关期刊论文 前1条
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
，本文编号：2511589
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