Spadaro Olga, Camell Christina D, Bosurgi Lidia, Nguyen Kim Y, Youm Yun-Hee, Rothlin Carla V, Dixit Vishwa Deep
Section of Comparative Medicine and Program on Integrative Cell Signaling and Neurobiology of Metabolism, Yale School of Medicine, New Haven, CT 06520, USA; Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA.
Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA.
Cell Rep. 2017 Apr 11;19(2):225-234. doi: 10.1016/j.celrep.2017.03.046.
In concert with their phagocytic activity, macrophages are thought to regulate the host immunometabolic responses primarily via their ability to produce specific cytokines and metabolites. Here, we show that IL-4-differentiated, M2-like macrophages secrete IGF1, a hormone previously thought to be exclusively produced from liver. Ablation of IGF1 receptors from myeloid cells reduced phagocytosis, increased macrophages in adipose tissue, elevated adiposity, lowered energy expenditure, and led to insulin resistance in mice fed a high-fat diet. The investigation of adipose macrophage phenotype in obese myeloid IGF1R knockout (MIKO) mice revealed a reduction in transcripts associated with M2-like macrophage activation. Furthermore, the MIKO mice infected with helminth Nippostrongylus brasiliensis displayed delayed resolution from infection with normal insulin sensitivity. Surprisingly, cold challenge did not trigger an overt M2-like state and failed to induce tyrosine hydroxylase expression in adipose tissue macrophages of control or MIKO mice. These results show that IGF1 signaling shapes the macrophage-activation phenotype.
与它们的吞噬活性协同作用，巨噬细胞被认为主要通过产生特定细胞因子和代谢产物的能力来调节宿主免疫代谢反应。在此，我们表明白细胞介素-4分化的M2样巨噬细胞分泌胰岛素样生长因子1（IGF1），一种先前被认为仅由肝脏产生的激素。从髓系细胞中去除IGF1受体可降低吞噬作用，增加脂肪组织中的巨噬细胞数量，提高肥胖程度，降低能量消耗，并导致高脂饮食喂养的小鼠出现胰岛素抵抗。对肥胖髓系IGF1受体敲除（MIKO）小鼠的脂肪巨噬细胞表型进行研究发现，与M2样巨噬细胞激活相关的转录本减少。此外，感染巴西日圆线虫的MIKO小鼠在感染后恢复延迟，但胰岛素敏感性正常。令人惊讶的是，冷刺激并未触发明显的M2样状态，且未能在对照或MIKO小鼠的脂肪组织巨噬细胞中诱导酪氨酸羟化酶表达。这些结果表明IGF1信号塑造了巨噬细胞激活表型。
