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TREML4 Promotes Inflammatory Programs in Human and Murine Macrophages and Alters Atherosclerosis Lesion Composition in the Apolipoprotein E Deficient Mouse.
Frontiers in Immunology ( IF 7.3 ) Pub Date : 2020-03-30 , DOI: 10.3389/fimmu.2020.00397
Marieli Gonzalez-Cotto 1 , Liang Guo 2 , Megan Karwan 3 , Shurjo K Sen 3 , Jennifer Barb 4 , Carlos J Collado 2 , Fathi Elloumi 5 , Erika M Palmieri 1 , Kimberly Boelte 1 , Frank D Kolodgie 3 , Aloke V Finn 3 , Leslie G Biesecker 6 , Daniel W McVicar 1
Affiliation  

The Triggering Receptor Expressed on Myeloid cells-like 4 (TREML4) is a member of the TREM receptor family, known modulators of inflammatory responses. We have previously found that TREML4 expression positively correlates with human coronary arterial calcification (CAC). However, the role of TREML4 in the pathogenesis of cardiovascular disease remains incompletely defined. Since macrophages play a key role in inflammatory conditions, we investigated if activated macrophages selectively expressed TREML4 and found that carriage of either one of the eQTL SNP's previously associated with increased TREML4 expression conferred higher expression in human inflammatory macrophages (M1) compared to alternatively activated macrophages (M2). Furthermore, we found that TREML4 expression in human M1 dysregulated several inflammatory pathways related to leukocyte activation, apoptosis and extracellular matrix degradation. Similarly, murine M1 expressed substantial levels of Treml4, as did oxLDL treated macrophages. Transcriptome analysis confirmed that murine Treml4 controls the expression of genes related to inflammation and lipid regulation pathways, suggesting a possible role in atherosclerosis. Analysis of Apoe-/-/Treml4-/- mice showed reduced plaque burden and lesion complexity as indicated by decreased stage scores, macrophage content and collagen deposition. Finally, transcriptome analysis of oxLDL-loaded murine macrophages showed that Treml4 represses a specific set of genes related to carbohydrate, ion and amino acid membrane transport. Metabolomic analysis confirmed that Treml4 deficiency may promote a beneficial relationship between iron homeostasis and glucose metabolism. Together, our results suggest that Treml4 plays a role in the development of cardiovascular disease, as indicated by Treml4-dependent dysregulation of macrophage inflammatory pathways, macrophage metabolism and promotion of vulnerability features in advanced lesions.

中文翻译:

TREML4促进人类和小鼠巨噬细胞的炎症程序,并改变载脂蛋白E缺乏症小鼠的动脉粥样硬化病变组成。

髓样细胞样4(TREML4)上表达的触发受体是TREM受体家族的成员,TREM受体家族是炎症反应的已知调节剂。我们先前已经发现TREML4表达与人冠状动脉钙化(CAC)正相关。但是,TREML4在心血管疾病的发病机理中的作用仍未完全确定。由于巨噬细胞在炎性疾病中起关键作用,因此我们研究了活化的巨噬细胞是否选择性表达TREML4,并且发现与先前激活的巨噬细胞相比,先前与TREML4表达增加相关的eQTL SNP之一的运输赋予人类炎性巨噬细胞更高的表达。 (M2)。此外,我们发现,人M1中的TREML4表达失调了与白细胞激活,凋亡和细胞外基质降解有关的几种炎症途径。同样,鼠M1和oxLDL处理的巨噬细胞也表达了大量的Treml4。转录组分析证实,鼠Treml4控制与炎症和脂质调节途径有关的基因的表达,表明在动脉粥样硬化中可能发挥作用。Apoe-/-/ Treml4-/-小鼠的分析显示,减少的斑块负担和病变的复杂性由降低的阶段评分,巨噬细胞含量和胶原沉积表示。最后,对载有oxLDL的小鼠巨噬细胞进行的转录组分析显示,Treml4抑制一组与碳水化合物,离子和氨基酸膜运输相关的基因。代谢组学分析证实Treml4缺乏可能促进铁稳态与葡萄糖代谢之间的有益关系。在一起,我们的研究结果表明Treml4在心血管疾病的发展中发挥作用,如Treml4依赖的巨噬细胞炎性途径失调,巨噬细胞代谢和促进晚期病变的脆弱性特征所表明。
更新日期:2020-03-30
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