Haematopoietic TLR4 deletion attenuates perivascular brown adipose tissue inflammation in atherosclerotic mice
Haematopoietic TLR4 deletion attenuates perivascular brown adipose tissue inflammation in atherosclerotic mice
复制标题
造血TLR4缺失减轻动脉粥样硬化小鼠血管周围棕色脂肪组织炎症
DOI：
10.1016/j.bbalip.2017.05.012
复制
发表时间：
2017-09-01
影响因子：
4.8
通讯作者：
Gao, Pingjin
中科院分区：
文献类型：
--
作者：
Liu, Penghao;Huang, Gaojian;Gao, Pingjin
目的：研究造血TLR 4缺失是否能减弱动脉粥样硬化小鼠血管周围棕色脂肪组织炎症反应。方法和结果：实验使用辐射LDL受体缺陷（LDLR-/-）小鼠与TLR 4缺陷（TLR 4（-/-））或年龄匹配的野生型（WT）小鼠骨髓。在喂食高胆固醇饮食12周后，与WT -> LDLR-/-小鼠相比，TLR 4（-/-）-> LDLR-/-小鼠在主动脉中发生的动脉粥样硬化病变较少。这种效应与血管周围脂肪组织（PVAT）中多室脂滴和线粒体的增加有关。免疫荧光分析证实，在TLR 4（-/-）-> LDLR-/-小鼠的局部PVAT中，毛细血管密度和M2巨噬细胞浸润增加，伴随着肿瘤坏死因子（TNF）-α表达的降低。体外研究表明，WT小鼠的骨髓源性巨噬细胞（BMDM）表现出M1样表型和棕榈酸诱导的炎性细胞因子表达。这些作用在从TLR 4（-/-）小鼠分离的BMDM中减弱。此外，与暴露于来自经棕榈酸酯处理的TLR 4（-/-）小鼠的BMDM的条件培养基（CM）的棕色脂肪细胞中观察到的那些相比，用源自经棕榈酸酯处理的BMDM的条件培养基（CM）孵育的棕色脂肪细胞表现出更大和更多的单室脂滴，并且棕色脂肪细胞特异性标志物和周脂蛋白-1的表达减少。这种降低的效力主要是由于TNF-α，所证明的TNF-α中和抗体的能力，以扭转这些effects.Conclusions：这些结果表明，造血特异性删除TLR 4促进PVAT稳态，这是参与减少巨噬细胞诱导的TNF-α分泌和增加线粒体生物合成棕色脂肪细胞。
Aims: To investigate whether haematopoietic TLR4 deletion attenuates perivascular brown adipose tissue inflammation in atherosclerotic mice.Methods and Results: Experiments were performed using irradiated LDL receptor-deficient (LDLR-/-) mice with marrow from either TLR4-deficient (TLR4(-/-)) or age-matched wild-type (WT) mice. After 12 weeks of being fed a high-cholesterol diet, TLR4(-/-) -> LDLR-/- mice developed fewer atherosclerotic lesions in the aorta compared to WT -> LDLR-/- mice. This effect was associated with an increase in multilocular lipid droplets and mitochondria in perivascular adipose tissue (PVAT). Immunofluorescence analysis confirmed that there was an increase in capillary density and M2 macrophage infiltration, accompanied by a decrease in tumour necrosis factor (TNF)-alpha expression in the localized PVAT of TLR4(-/-) -> LDLR-/- mice. In vitro studies indicated that bone marrow-derived macrophages (BMDMs) from WT mice demonstrated an M1-like phenotype and expression of inflammatory cytokines induced by palmitate. These effects were attenuated in BMDMs isolated from TLR4(-/-) mice. Furthermore, brown adipocytes incubated with conditioned medium (CM) derived from palmitate-treated BMDMs, exhibited larger and more unilocular lipid droplets, and reduced expression of brown adipocyte-specific markers and perilipin-1 compared to those observed in brown adipocytes exposed to CM from palmitate-treated BMDMs of TLR4(-/-) mice. This decreased potency was primarily due to TNF-alpha, as demonstrated by the capacity of the TNF-alpha neutralizing antibody to reverse these effects.Conclusions: These results suggest that haematopoietic-specific deletion of TLR4 promotes PVAT homeostasis, which is involved in reducing macrophage-induced TNF-alpha secretion and increasing mitochondrial biogenesis in brown adipocytes.