Mitochondrial STAT3 exacerbates LPS-induced sepsis by driving CPT1a-mediated fatty acid oxidation.
Mitochondrial STAT3 exacerbates LPS-induced sepsis by driving CPT1a-mediated fatty acid oxidation.
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DOI：
10.7150/thno.63751
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发表时间：
2022
期刊：
影响因子：
12.4
通讯作者：
Ikezoe T
中科院分区：
文献类型：
--
作者：
Li R;Li X;Zhao J;Meng F;Yao C;Bao E;Sun N;Chen X;Cheng W;Hua H;Li X;Wang B;Wang H;Pan X;You H;Yang J;Ikezoe T
基本原理：我们发现，一个子集的信号转导和转录激活因子3（STAT 3）易位到线粒体的吞噬细胞，包括巨噬细胞分离的个人与败血症。然而，线粒体STAT 3在巨噬细胞中的作用仍不清楚。方法：建立线粒体STAT 3基因敲入小鼠模型，研究线粒体STAT 3在体内的功能。随后在LPS诱导的脓毒症模型中进行细胞因子阵列分析、CBA分析、流式细胞术、免疫荧光染色和定量以及体内代谢分析。利用单细胞RNA测序、微阵列分析、代谢测定、质谱和ChIP测定来深入了解线粒体STAT 3在LPS诱导的脓毒症中代谢重编程的机制。结果如下：我们发现，线粒体STAT 3诱导NF-κB核定位，加重LPS诱导的脓毒症，同时代谢转换从主要使用葡萄糖到增加依赖脂肪酸氧化（FAO）。此外，线粒体STAT 3废除肉毒碱棕榈酰转移酶1a（CPT 1a）泛素化和降解LPS处理的巨噬细胞。同时，CPT 1a和泛素特异性肽酶50（USP 50）之间的相互作用被观察到。与此相反，敲低USP 50降低CPT 1a表达和线粒体STAT 3介导的FAO。ChIP检测显示NF-κB与USP 50启动子结合。姜黄素通过抑制线粒体STAT 3和NF-κB的活性减轻LPS介导的脓毒症。结论：我们的研究结果表明，线粒体STAT 3可以通过诱导巨噬细胞中USP 50介导的CPT 1a稳定化来触发FAO，至少部分是这样。
Rationale: We found that a subset of signal transducer and activator of transcription 3 (STAT3) translocated into mitochondria in phagocytes, including macrophages isolated from individuals with sepsis. However, the role of mitochondrial STAT3 in macrophages remains unclear. Method: To investigate the function of mitochondrial STAT3 in vivo, we generated inducible mitochondrial STAT3 knock-in mice. A cytokine array analysis, a CBA analysis, flow cytometry, immunofluorescence staining and quantification and metabolic analyses in vivo were subsequently performed in an LPS-induced sepsis model. Single-cell RNA sequencing, a microarray analysis, metabolic assays, mass spectrometry and ChIP assays were utilized to gain insight into the mechanisms of mitochondrial STAT3 in metabolic reprogramming in LPS-induced sepsis. Results: We found that mitochondrial STAT3 induced NF-κB nuclear localization and exacerbated LPS-induced sepsis in parallel with a metabolic switch from mainly using glucose to an increased reliance on fatty acid oxidation (FAO). Moreover, mitochondrial STAT3 abrogated carnitine palmitoyl transferase 1a (CPT1a) ubiquitination and degradation in LPS-treated macrophages. Meanwhile, an interaction between CPT1a and ubiquitin-specific peptidase 50 (USP50) was observed. In contrast, knocking down USP50 decreased CPT1a expression and FAO mediated by mitochondrial STAT3. The ChIP assays revealed that NF-κB bound the USP50 promoter. Curcumin alleviated LPS-mediated sepsis by suppressing the activities of mitochondrial STAT3 and NF-κB. Conclusion: Our findings reveal that mitochondrial STAT3 could trigger FAO by inducing CPT1a stabilization mediated by USP50 in macrophages, at least partially.