Interleukin-1β Activates a MYC-Dependent Metabolic Switch in Kidney Stromal Cells Necessary for Progressive Tubulointerstitial Fibrosis
Interleukin-1β Activates a MYC-Dependent Metabolic Switch in Kidney Stromal Cells Necessary for Progressive Tubulointerstitial Fibrosis
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DOI：
10.1681/asn.2017121283
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发表时间：
2018-06-01
影响因子：
13.6
通讯作者：
Duffield, Jeremy S.
中科院分区：
文献类型：
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作者：
Lemos, Dario R.;McMurdo, Michael;Duffield, Jeremy S.
背景肾损伤的特征在于持续的炎症和纤维化，然而炎症信号驱动纤维化的机制仍然不明确。方法CKD患者纤维化肾脏的RNA测序鉴定了代谢基因特征，包括线粒体和氧化磷酸化基因表达的丧失，伴随着PGC 1和MYC转录因子控制下糖酵解的调节剂和酶的增加，分别我们在体内模拟了这种代谢开关，在实验小鼠模型的肾损伤，并在体外在人肾基质细胞（SC）和人肾organoids.Results在小鼠中，MYC及其靶基因成为激活居民SC肾损伤后早期，表明急性先天免疫信号调节这种转录开关。在体外，用IL-1 β刺激纯化的人肾SC和人肾类器官重现了体内观察到的分子事件，诱导以增加MYC依赖性糖酵解为特征的功能性代谢紊乱，后者被证明是驱动增殖和基质产生所必需的。MYC直接与参与蛋白酶体降解的螯合体1/p62相互作用，并且p62表达的调节对MYC表达产生相反的影响。IL-1 β刺激自噬流，导致p62降解和MYC积累。抑制IL-1 R信号转导激酶IRAK 4在体内或抑制MYC在体内，以及在体外人肾类器官废除纤维化和减少tubular injury.Conclusions我们的研究结果定义了IL-1 β和代谢开关之间的连接在纤维化的启动和进展，并突出IL-1 β和MYC作为潜在的治疗目标在tubulointerstitial疾病。
Background Kidney injury is characterized by persisting inflammation and fibrosis, yet mechanisms by which inflammatory signals drive fibrogenesis remain poorly defined.Methods RNA sequencing of fibrotic kidneys from patients with CKD identified a metabolic gene signature comprising loss of mitochondrial and oxidative phosphorylation gene expression with a concomitant increase in regulators and enzymes of glycolysis under the control of PGC1 and MYC transcription factors, respectively. We modeled this metabolic switch in vivo, in experimental murine models of kidney injury, and in vitro in human kidney stromal cells (SCs) and human kidney organoids.Results In mice, MYC and the target genes thereof became activated in resident SCs early after kidney injury, suggesting that acute innate immune signals regulate this transcriptional switch. In vitro, stimulation of purified human kidney SCs and human kidney organoids with IL-1 beta recapitulated the molecular events observed in vivo, inducing functional metabolic derangement characterized by increased MYC-dependent glycolysis, the latter proving necessary to drive proliferation and matrix production. MYC interacted directly with sequestosome 1/p62, which is involved in proteasomal degradation, and modulation of p62 expression caused inverse effects on MYC expression. IL-1 beta stimulated autophagy flux, causing degradation of p62 and accumulation of MYC. Inhibition of the IL-1R signal transducer kinase IRAK4 in vivo or inhibition of MYC in vivo as well as in human kidney organoids in vitro abrogated fibrosis and reduced tubular injury.Conclusions Our findings define a connection between IL-1 beta and metabolic switch in fibrosis initiation and progression and highlight IL-1 beta and MYC as potential therapeutic targets in tubulointerstitial diseases.