Visceral adipose inflammation in obesity is associated with critical alterations in tregulatory cell numbers.
Visceral adipose inflammation in obesity is associated with critical alterations in tregulatory cell numbers.
复制标题
DOI：
10.1371/journal.pone.0016376
复制
发表时间：
2011-01-26
期刊：
影响因子：
3.7
通讯作者：
Rajagopalan S
中科院分区：
文献类型：
--
作者：
Deiuliis J;Shah Z;Shah N;Needleman B;Mikami D;Narula V;Perry K;Hazey J;Kampfrath T;Kollengode M;Sun Q;Satoskar AR;Lumeng C;Moffatt-Bruce S;Rajagopalan S
肥胖和2型糖尿病（DM）小鼠模型中胰岛素抵抗（IR）的发展特征是内脏脂肪中炎症巨噬细胞和T细胞亚群的进行性积聚。调节性T细胞（Tcells）可能通过与适应性和先天性免疫机制的相互作用在调节组织炎症中发挥关键作用。我们假设TcR的失衡是脂肪炎症的关键决定因素，并通过小鼠和人类的协调研究研究了TcR在IR/肥胖中的作用。 Foxp3-绿色荧光蛋白（GFP）"基因敲入"小鼠被随机分配至高脂饮食干预组，持续12周，以诱导DIO/IR。前瞻性招募无明显2型DM的病态肥胖者（n = 13）和瘦对照组（n = 7），以评估内脏脂肪炎症。 DIO可导致内脏脂肪中CD 3 + CD 4+和CD 3 + CD 8+细胞增加，内脏脂肪T淋巴细胞显著降低。内脏脂肪中的Treg数量与CD11b + CD11c+脂肪组织巨噬细胞（ATM）呈负相关。脾脏Treg数量随着归巢受体CXCR3和CCR7以及活化标志物CD44的上调而增加。体外分化测定显示，响应于来自炎性巨噬细胞的条件培养基，Treg分化受到抑制。病态肥胖的人内脏脂肪的特征在于CD11c + ATM的增加和foxp3表达的减少。我们的实验表明，小鼠和人的肥胖导致脂肪Treg耗竭。这些变化似乎是通过减少局部分化而不是受损的归巢发生的。我们的研究结果暗示了脂肪炎症的决定因素是TdR。
The development of insulin resistance (IR) in mouse models of obesity and type 2 diabetes mellitus (DM) is characterized by progressive accumulation of inflammatory macrophages and subpopulations of T cells in the visceral adipose. Regulatory T cells (Tregs) may play a critical role in modulating tissue inflammation via their interactions with both adaptive and innate immune mechanisms. We hypothesized that an imbalance in Tregs is a critical determinant of adipose inflammation and investigated the role of Tregs in IR/obesity through coordinated studies in mice and humans. Foxp3-green fluorescent protein (GFP) “knock-in” mice were randomized to a high-fat diet intervention for a duration of 12 weeks to induce DIO/IR. Morbidly obese humans without overt type 2 DM (n = 13) and lean controls (n = 7) were recruited prospectively for assessment of visceral adipose inflammation. DIO resulted in increased CD3+CD4+, and CD3+CD8+ cells in visceral adipose with a striking decrease in visceral adipose Tregs. Treg numbers in visceral adipose inversely correlated with CD11b+CD11c+ adipose tissue macrophages (ATMs). Splenic Treg numbers were increased with up-regulation of homing receptors CXCR3 and CCR7 and marker of activation CD44. In-vitro differentiation assays showed an inhibition of Treg differentiation in response to conditioned media from inflammatory macrophages. Human visceral adipose in morbid obesity was characterized by an increase in CD11c+ ATMs and a decrease in foxp3 expression. Our experiments indicate that obesity in mice and humans results in adipose Treg depletion. These changes appear to occur via reduced local differentiation rather than impaired homing. Our findings implicate a role for Tregs as determinants of adipose inflammation.
登录
查看更多内容
影响因子：
4.8
作者：
Pure, Ellen;Assoian, Richard K.
通讯作者：
Assoian, Richard K.
影响因子：
32.4
作者：
Fontenot, JD;Rasmussen, JP;Rudensky, AY
通讯作者：
Rudensky, AY
影响因子：
4.8
作者：
Barbi, Joseph;Snider, Heidi M.;Satoskar, Abhay R.
通讯作者：
Satoskar, Abhay R.
影响因子：
64.8
作者：
Sallusto, F;Lenig, D;Lanzavecchia, A
通讯作者：
Lanzavecchia, A
影响因子：
37.8
作者：
Combadiere, Christophe;Potteaux, Stephane;Mallat, Ziad
通讯作者：
Mallat, Ziad