The ligand-bound thyroid hormone receptor in macrophages ameliorates kidney injury via inhibition of nuclear factor-κB activities.
The ligand-bound thyroid hormone receptor in macrophages ameliorates kidney injury via inhibition of nuclear factor-κB activities.
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DOI：
10.1038/srep43960
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发表时间：
2017-03-08
影响因子：
4.6
通讯作者：
Kitamura K
中科院分区：
文献类型：
--
作者：
Furuya F;Ishii T;Tamura S;Takahashi K;Kobayashi H;Ichijo M;Takizawa S;Kaneshige M;Suzuki-Inoue K;Kitamura K
在慢性肾病（CKD）患者中，炎症在肾纤维化的进展中起着关键作用。甲状腺功能减退症与动脉粥样硬化和炎症的发生率增加有关，表明甲状腺激素及其受体对炎症过程的保护作用。甲状腺激素受体对巨噬细胞分化的作用还没有很好的记录。在这里，我们集中在巨噬细胞的内源性甲状腺激素受体α（TRα），并检查配体结合的TRα在巨噬细胞极化介导的抗炎作用中的作用。TRα缺陷的辐射嵌合小鼠在单侧输尿管梗阻模型中表现出加重的肾小管间质损伤。与野生型巨噬细胞相比，从缺乏TRα的小鼠梗阻肾脏中分离的巨噬细胞显示促炎细胞因子表达增加，伴有p65核转位增强。TRα缺陷骨髓源性巨噬细胞与野生型巨噬细胞的比较证实了前者细胞产生过量IL-1β水平的倾向。这些巨噬细胞与肾上皮细胞的共培养通过IL-1受体诱导了对上皮细胞更严重的损伤。我们的研究结果表明，巨噬细胞上的配体结合TRα通过抑制NF-κB通路在肾脏炎症中起保护作用，可能是通过影响控制CKD发展的促炎和抗炎平衡。
In chronic kidney disease (CKD) patients, inflammation plays a pivotal role in the progression of renal fibrosis. Hypothyroidism is associated with an increased occurrence of atherosclerosis and inflammation, suggesting protective roles of thyroid hormones and their receptors against inflammatory processes. The contribution of thyroid hormone receptors to macrophage differentiation has not been well documented. Here, we focused on the endogenous thyroid hormone receptor α (TRα) in macrophages and examined the role of ligand-bound TRα in macrophage polarization-mediated anti-inflammatory effects. TRα-deficient irradiated chimeric mice showed exacerbated tubulointerstitial injury in a unilateral ureteral obstruction model. Compared with wild-type macrophages, macrophages isolated from the obstructed kidneys of mice lacking TRα displayed increased expression of proinflammatory cytokines that was accompanied by enhanced nuclear translocation of p65. Comparison of TRα-deficient bone marrow-derived macrophages with wild-type macrophages confirmed the propensity of the former cells to produce excessive IL-1β levels. Co-culture of these macrophages with renal epithelial cells induced more severe damage to the epithelial cells via the IL-1 receptor. Our findings indicate that ligand-bound TRα on macrophages plays a protective role in kidney inflammation through the inhibition of NF-κB pathways, possibly by affecting the pro- and anti-inflammatory balance that controls the development of CKD.