From the National Heart and Lung Institute (A.S., Y.H., E.W., E.R.H.W., L.C., J.C.M., D.O.H., J.J.B.), Imperial College London Hammersmith Campus.
Molecular Sciences Research Hub, Imperial College London White City Campus (Y.H., E.W., E.R.H.W., L.J., N.J.L.).
Circ Res. 2020 Sep 11;127(7):928-944. doi: 10.1161/CIRCRESAHA.119.315528. Epub 2020 Jul 1.
The efficient resolution of tissue hemorrhage is an important homeostatic function. In human macrophages in vitro, heme activates an AMPK (AMP-activated protein kinase)/ATF1 (activating transcription factor-1) pathway that directs Mhem macrophages through coregulation of HO-1 (heme oxygenase-1; ) and lipid homeostasis genes.
We asked whether this pathway had an in vivo role in mice.
Perifemoral hematomas were used as a model of hematoma resolution. In mouse bone marrow-derived macrophages, heme induced HO-1, lipid regulatory genes including LXR (lipid X receptor), the growth factor IGF1 (insulin-like growth factor-1), and the splenic red pulp macrophage gene . This response was lost in bone marrow-derived macrophages from mice deficient in AMPK () or ATF1 (). In vivo, femoral hematomas resolved completely between days 8 and 9 in littermate control mice (n=12), but were still present at day 9 in mice deficient in either AMPK () or ATF1 (; n=6 each). Residual hematomas were accompanied by increased macrophage infiltration, inflammatory activation and oxidative stress. We also found that fluorescent lipids and a fluorescent iron-analog were trafficked to lipid-laden and iron-laden macrophages respectively. Moreover erythrocyte iron and lipid abnormally colocalized in the same macrophages in mice. Therefore, iron-lipid separation was -dependent.
Taken together, these data demonstrate that both AMPK and ATF1 are required for normal hematoma resolution. Graphic Abstract: An online graphic abstract is available for this article.
组织出血的有效解决是重要的体内平衡功能。在体外人类巨噬细胞中，血红素激活 AMPK（AMP 激活的蛋白激酶）/ATF1（激活转录因子 1）途径，通过 HO-1（血红素加氧酶-1；）和脂质稳态基因的共同调控，指导 Mhem 巨噬细胞。
我们询问该途径在小鼠体内是否具有作用。
外周血肿被用作血肿溶解的模型。在小鼠骨髓来源的巨噬细胞中，血红素诱导 HO-1、脂质调节基因，包括 LXR（脂质 X 受体）、生长因子 IGF1（胰岛素样生长因子 1）和脾脏红髓巨噬细胞基因。在 AMPK（）或 ATF1（）缺失的小鼠的骨髓来源的巨噬细胞中，这种反应消失了。在体内，同窝对照小鼠的股骨干血肿在第 8 天至第 9 天完全溶解（n=12），但 AMPK（）或 ATF1（）缺失的小鼠的血肿仍存在第 9 天（n=6 只）。残留的血肿伴有巨噬细胞浸润增加、炎症激活和氧化应激。我们还发现荧光脂质和荧光铁类似物分别被转运到富含脂质和富含铁的巨噬细胞中。此外，在 小鼠中，红细胞铁和脂质异常地在同一巨噬细胞中聚集。因此，铁-脂质分离是 AMPK 和 ATF1 依赖性的。
总之，这些数据表明 AMPK 和 ATF1 对于正常血肿溶解都是必需的。
