Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Sci Adv. 2019 Oct 23;5(10):eaax4895. doi: 10.1126/sciadv.aax4895. eCollection 2019 Oct.
Targeting hypoxia-sensitive pathways in immune cells is of interest in treating diseases. Here, we demonstrate that physiologic hypoxia (1% O), as encountered in bone marrow and spleen, accelerates human M2 macrophage efferocytosis of apoptotic-neutrophils and senescent erythrocytes via lipolysis-dependent biosynthesis of specialized pro-resolving mediators (SPMs), i.e. resolvins, protectins, maresins and lipoxin. SPM-production was enhanced via hypoxia in M2 macrophages interacting with neutrophils and erythrocytes enabling structural elucidation of a novel eicosapentaenoic acid (EPA)-derived resolvin, resolvin E4 (RvE4) that stimulates efferocytosis of senescent erythrocytes and more potently than aspirin in mouse hemorrhagic exudates. In hypoxia, glycolysis inhibition enhanced neutrophil RvE4-SPM biosynthesis. Human macrophage-erythrocyte co-incubations in physiologic hypoxia produced RvE4-SPM from erythrocyte stores of omega-3 fatty acids. These results indicate that hypoxic environments, including bone marrow and spleen as well as sites of inflammation, activate SPM-biosynthetic circuits that in turn stimulate resolution and clearance of senescent erythrocytes and apoptotic neutrophils.
靶向免疫细胞中的缺氧敏感途径在治疗疾病方面具有重要意义。在这里，我们证明了骨髓和脾脏中遇到的生理性缺氧（1% O2）通过脂解依赖性合成专门的促解决介质（SPM），即 resolvins、protectins、maresins 和 lipoxin，加速了人 M2 巨噬细胞对凋亡中性粒细胞和衰老红细胞的吞噬作用。SPM 的产生通过与中性粒细胞和红细胞相互作用的 M2 巨噬细胞中的缺氧增强，从而能够对一种新型的二十碳五烯酸（EPA）衍生的 resolvin，即 resolvin E4（RvE4）进行结构阐明，该 resolvin 刺激衰老红细胞的吞噬作用，并且在小鼠出血性渗出物中的作用比阿司匹林更强。在缺氧条件下，糖酵解抑制增强了中性粒细胞 RvE4-SPM 的生物合成。在生理性缺氧下，人巨噬细胞-红细胞共培养物从红细胞的 ω-3 脂肪酸储存中产生 RvE4-SPM。这些结果表明，包括骨髓和脾脏以及炎症部位在内的缺氧环境激活了 SPM 生物合成途径，从而反过来刺激衰老红细胞和凋亡中性粒细胞的解决和清除。
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