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首页> 外文期刊>Autophagy >The autophagy receptor SQSTM1/p62 mediates anti-inflammatory actions of the selective NR3C1/glucocorticoid receptor modulator compound A (CpdA) in macrophages
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The autophagy receptor SQSTM1/p62 mediates anti-inflammatory actions of the selective NR3C1/glucocorticoid receptor modulator compound A (CpdA) in macrophages

机译：自噬受体Sqstm1 / p62在巨噬细胞中介导选择性NR3C1 /糖皮质激素受体调节剂A（CPDA）的抗炎作用

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Glucocorticoids are widely used to treat inflammatory disorders; however, prolonged use of glucocorticoids results in side effects including osteoporosis, diabetes and obesity. Compound A (CpdA), identified as a selective NR3C1/glucocorticoid receptor (nuclear receptor subfamily 3, group C, member 1) modulator, exhibits an inflammation-suppressive effect, largely in the absence of detrimental side effects. To understand the mechanistic differences between the classic glucocorticoid dexamethasone (DEX) and CpdA, we looked for proteins oppositely regulated in bone marrow-derived macrophages using an unbiased proteomics approach. We found that the autophagy receptor SQSTM1 but not NR3C1 mediates the anti-inflammatory action of CpdA. CpdA drives SQSTM1 upregulation by recruiting the NFE2L2 transcription factor to its promoter. In contrast, the classic NR3C1 ligand dexamethasone recruits NR3C1 to the Sqstm1 promoter and other NFE2L2-controlled gene promoters, resulting in gene downregulation. Both DEX and CpdA induce autophagy, with marked different autophagy characteristics and morphology. Suppression of LPS-induced Il6 and Ccl2 genes by CpdA in macrophages is hampered upon Sqstm1 silencing, confirming that SQSTM1 is essential for the anti-inflammatory capacity of CpdA, at least in this cell type. Together, these results demonstrate how off-target mechanisms of selective NR3C1 ligands may contribute to a more efficient anti-inflammatory therapy.
机译：糖皮质激素被广泛用于治疗炎症性疾病;然而，长期使用糖皮质激素导致副作用，包括骨质疏松症，糖尿病和肥胖症。鉴定为选择性NR3C1 /糖皮质激素受体（核受体亚家草3，C组，成员1）调节剂的化合物A（CPDA）表现出炎症抑制作用，主要是在没有有害副作用的情况下。为了了解经典糖皮质激素地塞米松（DEX）和CPDA之间的机械差异，我们使用无偏的蛋白质组学方法寻找与骨髓衍生的巨噬细胞相反调节的蛋白质。我们发现自噬受体Sqstm1但不是NR3C1介导CPDA的抗炎作用。 CPDA通过将NFE2L2转录因子招募到其启动子来驱动SQSTM1 Upregulation。相反，经典NR3C1配体地塞米松促进NR3C1至SQSTM1启动子和其他NFE2L2受控基因启动子，导致基因下调。 DEX和CPDA均诱导自噬，具有明显不同的自噬和形态。在巨噬细胞中，CPDA抑制LPS诱导的IL6和CCL2基因在SQSTM1沉默时受到阻碍，确认SQSTM1至少在该细胞类型中对CPDA的抗炎能力至关重要。这些结果一起表明了选择性NR3C1配体的脱靶机制如何有助于更有效的抗炎疗法。

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