Glucocorticoids enhance prolonged clearance of apoptotic cells by upregulating liver X receptor, peroxisome proliferator-activated receptor-δ and UCP2
Glucocorticoids enhance prolonged clearance of apoptotic cells by upregulating liver X receptor, peroxisome proliferator-activated receptor-δ and UCP2
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DOI：
10.1016/j.bbamcr.2014.12.014
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发表时间：
2015-03-01
影响因子：
5.1
通讯作者：
Szondy, Zsuzsa
中科院分区：
文献类型：
--
作者：
Garabuczi, Eva;Sarang, Zsolt;Szondy, Zsuzsa
有效的吞噬细胞清除凋亡细胞（efferocytosis）对于预防慢性炎症和自身免疫的发展至关重要。糖皮质激素广泛用于慢性炎症性疾病的治疗，越来越多的证据表明，它们的部分作用是通过增强巨噬细胞的efferocytosis。糖皮质激素先前被证明可以促进蛋白质和mfg - e8依赖性的efferocytosis。由于我们实验室之前的研究表明，糖皮质激素诱导巨噬细胞中视黄醛脱氢酶的表达，因此在本实验中，我们在小鼠骨髓源性巨噬细胞中研究了类维甲酸可能参与糖皮质激素诱导的efferocytosis。在这里，我们表明糖皮质激素不仅促进短期，而且还促进凋亡细胞的长期清除。糖皮质激素似乎可以直接诱导吞噬相关基因MERTK、C1q、UCP2和转录因子C/EBP β的表达。C/EBP β有助于进一步诱导吞噬相关基因，并且是诱导脂敏感受体LXRs、PPAR delta、RAR α、RXR α和RALDH1所必需的，后者以lxr和RAR α依赖的方式存在。糖皮质激素诱导的长期efferocylosis增强依赖于脂质感知受体的诱导，已知脂质感知受体由被吞噬细胞的脂质含量触发，以增强吞噬能力。类维甲酸不影响糖皮质激素诱导的凋亡细胞的短期吞噬，但通过促进有效的LXR和PPAR δ上调，类维甲酸在糖皮质激素诱导的长时间清除凋亡细胞过程中增强efferocytosis是必需的。我们的数据表明，类维甲酸可以被认为是糖皮质激素治疗炎症性疾病疗效的潜在促进剂。(C) 2014 Elsevier B.V.版权所有
Efficient phagocytic clearance of apoptotic cells (efferocytosis) is essential to prevent the development of chronic inflammation and autoimmunity. Glucocorticoids are widely used in the therapy of chronic inflammatory diseases, and increasing evidence suggests that they act partly via enhancing efferocytosis by macrophages. Glucocorticoids were previously shown to promote both protein S-and MFG-E8-dependent efferocytosis. Since previous studies in our laboratory have demonstrated that glucocorticoids induce the expression of retinaldehyde dehydrogenases in macrophages, in the present experiments the possible involvement of retinoids in the glucocorticoid-induced efferocytosis was studied in mouse bone marrow derived macrophages. Here we show that glucocorticoids promote not only short-term, but also long-term clearance of apoptotic cells. Glucocorticoids seem to directly induce the expression of the phagocytosis-related genes MERTK, C1q, UCP2, and the transcription factor C/EBP beta. C/EBP beta contributes to the further induction of the phagocytosis-related genes, and is required for the induction of lipid sensing receptors LXRs, PPAR delta, RAR alpha, RXR alpha and RALDH1, the latter one in an LXR-and RAR alpha-dependent manner. Glucocorticoid-induced enhancement in long-term efferocytosis was dependent on the induction of lipid sensing receptors known to be triggered by the lipid content of the engulfed cells to enhance phagocytic capacity. Retinoids did not affect the glucocorticoid-induced short term phagocytosis of apoptotic cells, but were required for the glucocorticoid-induced enhancement of efferocytosis during prolonged clearance of apoptotic cells by promoting efficient LXR and PPAR delta upregulation. Our data indicate that retinoids could be considered as potential promoters of the efficacy of glucocorticoid treatment in inflammatory diseases. (C) 2014 Elsevier B.V. All rights reserved.