Oxidized Phospholipid oxPAPC Alters Regulatory T-Cell Differentiation and Decreases Their Protective Function in Atherosclerosis in Mice.
Oxidized Phospholipid oxPAPC Alters Regulatory T-Cell Differentiation and Decreases Their Protective Function in Atherosclerosis in Mice.
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氧化磷脂 oxPAPC 改变调节性 T 细胞分化并降低其对动脉粥样硬化小鼠的保护功能。
DOI：
10.1161/atvbaha.123.319674
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Major,AmyS
中科院分区：
文献类型：
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作者：
Appleton,BrennaD;Palmer,SydneyA;Smith,HarrisonP;Stephens,LillyE;Major,AmyS
背景调节性T细胞(Tregs)在动脉粥样硬化中具有保护作用，但在疾病进展过程中由于细胞死亡和稳定性丧失而减少。然而，三叉神经功能障碍的机制仍不清楚。氧化磷脂在动脉粥样硬化中含量丰富，可以激活天然免疫细胞，但对其对T细胞的影响知之甚少。鉴于动脉粥样硬化进展过程中的Treg损失和斑块微环境中氧化磷脂的水平，我们研究了与动脉粥样硬化相关的氧化型磷脂1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine(OxPAPC)是否改变了Treg的分化和功能。方法用流式细胞仪检测有或没有oxPAPC的T细胞分化为Treg、辅助性T细胞(Th)1和Th17细胞。通过批量RNA测序分析oxPAPC处理的Tregs的基因表达。结果与对照组相比，oxPAPC诱导的Tres活性降低，但存活细胞表达更高水平的Th1相关标志物T-bet、CXCR3和干扰素-γ。OxPAPC对Th1和Th17偏斜培养无明显影响。干扰素-γ与T细胞不稳定有关，因此使用Ifngr1−/−+T细胞重复T细胞极化实验。干扰素γR1(干扰素γ受体1)缺失并不能提高oxPAPC处理的Treg细胞的存活率；然而，存活细胞中T-bet和干扰素-γ的表达并没有增加，提示干扰素-γ信号的作用。OxPAPC处理的Treg在体外的抑制作用较弱，在高脂Ldlr−/−小鼠中的过继转移研究表明oxPAPC诱导的Treg改变了组织归巢，不足以抑制动脉粥样硬化的进展。结论oxPAPC诱导Treg特异性的变化改变Treg的分化并部分通过干扰素-γ信号诱导存活细胞的Th1型表型。这在生物学上是相关的，因为oxPAPC治疗的Tregs不能减少Ldlr−/−小鼠的动脉粥样硬化进展。这项研究支持氧化磷脂在对T细胞分化和动脉粥样硬化保护功能产生负面影响方面的作用。
BACKGROUNDRegulatory T cells (Tregs) are protective in atherosclerosis but reduced during disease progression due to cell death and loss of stability. However, the mechanisms of Tregdysfunction remain unknown. Oxidized phospholipids are abundant in atherosclerosis and can activate innate immune cells, but little is known regarding their impact on T cells. Given Tregloss during atherosclerosis progression and oxidized phospholipid levels in the plaque microenvironment, we investigated whether oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (oxPAPC), an oxidized phospholipid associated with atherosclerotic plaques, alters Tregdifferentiation and function.METHODSCD4+T cells were polarized to Treg, T helper (Th) 1, and Th17 cells with or without oxPAPC and assessed by flow cytometry. Gene expression in oxPAPC-treated Tregswas analyzed by bulk RNA sequencing. Functional studies of oxPAPC-induced Tregswere performed by coculturing Tregswith CellTrace Violet–labeled cells in vitro, and by adoptively transferring Tregsto hyperlipidemicLdlr−/−mice to measure atherosclerosis progression.RESULTSCompared with controls, oxPAPC-treated Tregswere less viable, but surviving cells expressed higher levels of the Th1-associated markers T-bet, CXCR3, and IFN (interferon)-γ. Th1 and Th17 skewing cultures were unaltered by oxPAPC. IFN-γ is linked to Treginstability, thus Tregpolarization experiments were repeated usingIfngr1−/−CD4+T cells. IFNγR1 (INF gamma receptor 1) deficiency did not improve cell viability in oxPAPC-treated Tregs; however, T-bet and IFN-γ expression was not increased in surviving cells suggesting a role for IFN-γsignaling. OxPAPC-treated Tregswere less suppressive in vitro, and adoptive transfer studies in hyperlipidemicLdlr−/−mice showed that oxPAPC-induced Tregspossessed altered tissue homing and were insufficient to inhibit atherosclerosis progression.CONCLUSIONSOxPAPC elicits Treg-specific changes altering Tregdifferentiation and inducing a Th1-like phenotype in surviving cells partially through IFN-γ signaling. This is biologically relevant as oxPAPC-treated Tregsdo not reduce atherosclerosis progression inLdlr−/−mice. This study supports the role of oxidized phospholipids in negatively impacting Tregdifferentiation and atheroprotective function.