【作者】 戴菱菱；

【导师】 周宏灏；

【作者基本信息】 中南大学 ， 临床药理学， 2013， 博士

【摘要】 巨噬细胞是参与机体先天性免疫与细胞免疫的重要的免疫细胞,它们与树突细胞以及其他各种效应细胞组成了人类抵御外界侵害的屏障。根据其活化状态、细胞表型及功能的差异,可大致分为经典激活的巨噬细胞(M1型)及替代激活的巨噬细胞(M2型)。肥胖症是21世纪威胁人类健康的主要原因之一。肥胖常伴随着一系列的代谢性疾病,包括胰岛素抵抗、Ⅱ型糖尿病、脂肪肝、动脉粥样硬化及高血压等,这些疾病的发生大多是由慢性炎症引起,而在慢性炎症中巨噬细胞具有举足轻重的地位。目前发现,白色脂肪组织的M2型巨噬细胞的激活可减少肥胖所引起的炎症反应以及胰岛素抵抗,其机制目前尚不明确。本课题研究发现M2型巨噬细胞可发挥抗自身死亡的重要生理功能,该生理功能一定程度上可以解释M2型巨噬细胞在肥胖症中对机体的保护机制。具体的研究成果如下：1.通过比较M2型巨噬细胞诱导剂白细胞介素-4(IL-4)以及过氧化物酶体增殖物激活受体δ/γ(PPARδ/PPARγ)的激动剂所引起的基因表达的改变,我们发现M2型巨噬细胞可参与促细胞存活、抗细胞死亡的调控过程。PPARδ/y也同时参与调控脂肪酸的生成、氧化、运输以及贮存。2.在体外,PPARδ/y或STAT6在巨噬细胞中的敲除可促进棕榈酸所引起的巨噬细胞死亡,在体内,高脂饮食或者β-肾上腺素能受体激动剂所引发的脂解效应使得骨髓细胞PPARδ/γ特异性敲除的小鼠(Mac-PPARδ/γ-/-)以及STAT6全身性敲除小鼠(STAT6-/-)的脂肪组织巨噬细胞表现出更多的半胱天冬酶-3活性。3. Angiopoietin-like4(Angptl4)以及neurogenic locus notch homolog protein4(Notch4)是PPARs/STAT6下游抗细胞死亡通路的靶点基因,Angpt14或Notch4的敲除可促进棕榈酸催化的巨噬细胞凋亡。4.巨噬细胞死亡可引起其自身炎症反应,并通过炎症因子的释放,促进其他巨噬细胞与脂肪细胞的炎性反应的发生,这可能是肥胖症中脂肪组织炎症反应发生的根源之一。更多还原

【Abstract】 Immune cells, such as macrophages, dendritic cells and a number of other effector cells are involved in the important human host mechanism against external threats. Macrophages function in both innate (non-specific) and adaptive (specific) immunity in vertebrate animals. Based on their functional importance, they can be divided into classically activated macrophages (also known as M1) and alternatively activated macrophages (also known as M2).Obesity is one of the major threats to human health in the21st century. It presents a low grade inflammatory and can progress to other metabolic diseases including insulin resistance, type II diabetes, fatty liver, atherosclerosis and hypertension. Recent evidence indicates that macrophages are key players in the progression of metabolic diseases.Alternative activation of adipose tissue resident macrophages (ATM) reduces obesity-induced metabolic inflammation and insulin resistance. The molecular detail of this protective effect remains unclear. Here we show that alternatively activated (M2) macrophages are protected from cellular dysfunction caused by lipid overload which can, at least partially explain the protective effect of M2macrophages during obesity. The major findings in this paper are:1. Cross-comparisons of genes regulated two M2inducers, interleukin-4(IL-4) or peroxisome proliferator-activated receptor delta/gamma (PPARs/PPARy) agonists, reveal that alternative activation promotes the cell survival program while inhibiting that of apoptosis. PPAR signaling also controls pathways that direct fatty acids toward storage, oxidation and biosynthesis of lipid mediators.2. In cultured macrophages, deletion of PPARδ/PPARγ or (signal transducer and activator of transcription6) STAT6(a downstream effector of IL-4) genes increases the susceptibility to palmitic acid-induced necrotic cell death. In concert, higher levels of caspase-3activities are detected in ATMs derived from myeloid-specific PPARδ/γ-/-or STAT6-/-mice either challenged with a high fat diet or p-adrenergic agonist.3. At the molecular level, Angptl4and Notch4are identified as PPAR targets in the survival pathway. Angptl4-/-or Notch4-/-macrophages are shown to be more prone to death after palmitic acid treatment.4. Palmitic acid induced macrophage death is sufficient to cause inflammatory response and this response can be amplified by crosstalk between macrophages and adipocytes, which may contribute to the initiation of inflammation during obesity.更多还原