ApoE expression in macrophages communicates immunometabolic signaling that controls hyperlipidemia-driven hematopoiesis & inflammation via extracellular vesicles.
ApoE expression in macrophages communicates immunometabolic signaling that controls hyperlipidemia-driven hematopoiesis & inflammation via extracellular vesicles.
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DOI：
10.1002/jev2.12345
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发表时间：
2023-08
影响因子：
16
通讯作者：
中科院分区：
文献类型：
--
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虽然骨髓细胞表达载脂蛋白E（apoE）被认为可以控制炎症，但这种益处是否可以通过细胞外囊泡传递尚不清楚。通过研究野生型（WT-BMDM-EV）和ApoE缺陷型（EKO-BMDM-EV）小鼠骨髓巨噬细胞产生的细胞外囊泡，我们发现apoE表达在调节其细胞信号传导特性中的关键作用。WT-BMDM-EV通过增加apoE和miR-146 a-5 p的细胞水平，降低NF-κB信号传导，将抗炎特性传递给受体骨髓细胞。他们还下调了miR-142 a-3 p的细胞水平，导致其靶点肉毒碱棕榈酰转移酶1A（CPT 1A）的水平增加，从而改善受体细胞中的脂肪酸氧化（FAO）和氧化磷酸化（OxPHOS）。这种有利的代谢极化增强了细胞表面MerTK水平和凋亡细胞的吞噬摄取。相反，EKO-BMDM-EV通过降低apoE和miR-146 a-5 p的细胞水平发挥相反的作用，这增加了NF-κB−驱动的GLUT 1介导的葡萄糖摄取、有氧糖酵解和氧化应激。此外，EKO-BMDM-EV增加了细胞miR-142 a-3 p水平，这降低了受体骨髓细胞中的CPT 1A水平并损害了FAO和OxPHOS。当与幼稚的CD 4 + T淋巴细胞一起培养时，EKO‐BMDM‐EV驱动它们的活化和增殖，并促进它们向Th 1表型的转变。虽然将WT-BMDM-EV输注到高脂血症小鼠中解决了炎症，但EKO-BMDM-EV的输注增加了造血并驱动了骨髓细胞和T淋巴细胞中的炎症反应。巨噬细胞细胞外囊泡的ApoE依赖性免疫代谢信号传导依赖于由miR-146 a-5 p和miR-142 a-3 p控制的转录轴，可以通过将miR-146 a模拟物和miR-142 a拮抗剂输注到高脂血症apoE缺陷小鼠中来复制。总之，我们的研究结果揭示了一个新的属性apoE表达的巨噬细胞，调节其分泌的细胞外囊泡的免疫代谢调节特性。
While apolipoprotein E (apoE) expression by myeloid cells is recognized to control inflammation, whether such benefits can be communicated via extracellular vesicles is not known. Through the study of extracellular vesicles produced by macrophages derived from the bone marrow of Wildtype (WT‐BMDM‐EV) and ApoE deficient (EKO‐BMDM‐EV) mice, we uncovered a critical role for apoE expression in regulating their cell signaling properties. WT‐BMDM‐EV communicated anti‐inflammatory properties to recipient myeloid cells by increasing cellular levels of apoE and miR‐146a‐5p, that reduced NF‐κB signalling. They also downregulated cellular levels of miR‐142a‐3p, resulting in increased levels of its target carnitine palmitoyl transferase 1A (CPT1A) which improved fatty acid oxidation (FAO) and oxidative phosphorylation (OxPHOS) in recipient cells. Such favorable metabolic polarization enhanced cell‐surface MerTK levels and the phagocytic uptake of apoptotic cells. In contrast, EKO‐BMDM‐EV exerted opposite effects by reducing cellular levels of apoE and miR‐146a‐5p, which increased NF‐κB−driven GLUT1‐mediated glucose uptake, aerobic glycolysis, and oxidative stress. Furthermore, EKO‐BMDM‐EV increased cellular miR‐142a‐3p levels, which reduced CPT1A levels and impaired FAO and OxPHOS in recipient myeloid cells. When cultured with naïve CD4+ T lymphocytes, EKO‐BMDM‐EV drove their activation and proliferation, and fostered their transition to a Th1 phenotype. While infusions of WT‐BMDM‐EV into hyperlipidemic mice resolved inflammation, infusions of EKO‐BMDM‐EV increased hematopoiesis and drove inflammatory responses in myeloid cells and T lymphocytes. ApoE‐dependent immunometabolic signaling by macrophage extracellular vesicles was dependent on transcriptional axes controlled by miR‐146a‐5p and miR‐142a‐3p that could be reproduced by infusing miR‐146a mimics & miR‐142a antagonists into hyperlipidemic apoE‐deficient mice. Together, our findings unveil a novel property for apoE expression in macrophages that modulates the immunometabolic regulatory properties of their secreted extracellular vesicles.
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