Institute of Anatomy, Leipzig University, Liebigstraße 13, 04103, Leipzig, Germany.
Diabetologia. 2014 Mar;57(3):562-71. doi: 10.1007/s00125-013-3139-y. Epub 2013 Dec 17.
AIMS/HYPOTHESIS: Obesity is frequently associated with low-grade inflammation of adipose tissue (AT), and the increase in adipose tissue macrophages (ATMs) is linked to an increased risk of type 2 diabetes. Macrophages have been regarded as post-mitotic, but recent observations have challenged this view. In this study, we tested the hypothesis that macrophages proliferate within AT in diet-induced obesity in mice and humans.
We studied the expression of proliferation markers by immunofluorescence, PCR and flow cytometry in three different models of mouse obesity as well as in humans (n = 239). The cell fate of dividing macrophages was assessed by live imaging of AT explants.
We show that ATMs undergo mitosis within AT, predominantly within crown-like structures (CLS). We found a time-dependent increase in ATM proliferation when mice were fed a high-fat diet. Upregulation of CD206 and CD301 in proliferating ATMs indicated preferential M2 polarisation. Live imaging within AT explants from mice revealed that macrophages emigrate out of the CLS to become resident in the interstitium. In humans, we confirmed the increased expression of proliferation markers of CD68(+) macrophages in CLS and demonstrated a higher mRNA expression of the proliferation marker Ki67 in AT from obese patients.
CONCLUSIONS/INTERPRETATION: Local proliferation contributes to the increase in M2 macrophages in AT. Our data confirm CLS as the primary site of proliferation and a new source of ATMs and support a model of different recruitment mechanisms for classically activated (M1) and alternatively activated (M2) macrophages in obesity.
目的/假设：肥胖通常与脂肪组织（AT）的低度炎症有关，脂肪组织巨噬细胞（ATMs）的增加与 2 型糖尿病风险的增加有关。巨噬细胞被认为是有丝分裂后细胞，但最近的观察结果对这一观点提出了挑战。在这项研究中，我们测试了以下假设，即在小鼠和人类的饮食诱导肥胖中，巨噬细胞在脂肪组织内增殖。
我们通过免疫荧光、PCR 和流式细胞术研究了三种不同的小鼠肥胖模型以及人类（n=239）中增殖标志物的表达。通过对脂肪组织外植体的活体成像来评估分裂巨噬细胞的细胞命运。
我们表明，ATMs 在 AT 内经历有丝分裂，主要在冠状结构（CLS）内。当小鼠喂食高脂肪饮食时，我们发现 ATMs 的增殖呈时间依赖性增加。增殖 ATMs 中 CD206 和 CD301 的上调表明优先向 M2 极化。来自小鼠的 AT 外植体的活体成像显示，巨噬细胞从 CLS 迁出并成为间质的常驻细胞。在人类中，我们证实了 CLS 中 CD68（+）巨噬细胞增殖标志物的表达增加，并证明了肥胖患者的 AT 中增殖标志物 Ki67 的 mRNA 表达更高。
结论/解释：局部增殖有助于 AT 中 M2 巨噬细胞的增加。我们的数据证实了 CLS 是增殖的主要部位和 ATMs 的新来源，并支持肥胖中经典激活（M1）和替代激活（M2）巨噬细胞不同募集机制的模型。
