Beneke Angelika, Guentsch Annemarie, Hillemann Annette, Zieseniss Anke, Swain Lija, Katschinski Dörthe M
Institute of Cardiovascular Physiology, University Medical Center, Göttingen, Germany.
Cell Death Dis. 2017 Aug 10;8(8):e2976. doi: 10.1038/cddis.2017.375.
Macrophages are essential for the inflammatory response after an ischemic insult and thereby influence tissue recovery. For the oxygen sensing prolyl-4-hydroxylase domain enzyme (PHD) 2 a clear impact on the macrophage-mediated arteriogenic response after hind-limb ischemia has been demonstrated previously, which involves fine tuning a M2-like macrophage population. To analyze the role of PHD3 in macrophages, we performed hind-limb ischemia (ligation and excision of the femoral artery) in myeloid-specific PHD3 knockout mice (PHD3) and analyzed the inflammatory cell invasion, reperfusion recovery and fibrosis in the ischemic muscle post-surgery. In contrast to PHD2, reperfusion recovery and angiogenesis was unaltered in PHD3 compared to WT mice. Macrophages from PHD3 mice showed, however, a dampened inflammatory reaction in the affected skeletal muscle tissues compared to WT controls. This was associated with a decrease in fibrosis and an anti-inflammatory phenotype of the PHD3 macrophages, as well as decreased expression of Cyp2s1 and increased PGE2-secretion, which could be mimicked by PHD3 bone marrow-derived macrophages in serum starvation.
巨噬细胞对于缺血性损伤后的炎症反应至关重要，从而影响组织恢复。对于氧感应脯氨酰-4-羟化酶结构域酶（PHD）2，先前已证明其对后肢缺血后巨噬细胞介导的动脉生成反应有明显影响，这涉及对M2样巨噬细胞群体的微调。为了分析PHD3在巨噬细胞中的作用，我们在骨髓特异性PHD3基因敲除小鼠（PHD3−/−）中进行了后肢缺血（结扎和切除股动脉），并分析了术后缺血肌肉中的炎性细胞浸润、再灌注恢复和纤维化情况。与PHD2不同，与野生型小鼠相比，PHD3−/−小鼠的再灌注恢复和血管生成未发生改变。然而，与野生型对照相比，来自PHD3−/−小鼠的巨噬细胞在受影响的骨骼肌组织中表现出减弱的炎症反应。这与纤维化的减少、PHD3−/−巨噬细胞的抗炎表型以及Cyp2s1表达的降低和PGE2分泌的增加有关，血清饥饿条件下PHD3−/−骨髓来源的巨噬细胞可模拟这种情况。
