Rationale: Chronic inflammation is central in the development of atherosclerosis. Both innate and adaptive immunities are involved. Although several studies have evaluated the functions of natural killer (NK) cells in experimental animal models of atherosclerosis, it is not yet clear whether NK cells behave as protective or proatherogenic effectors. One of the main caveats of previous studies was the lack of specificity in targeting loss or gain of function of NK cells.

Objectives: We used 2 selective genetic approaches to investigate the role of NK cells in atherosclerosis: (1) Ncr1^iCre/+R26^lsl−DTA/+ mice in which NK cells were depleted and (2) Noé mice in which NK cells are hyperresponsive.

Methods and Results: No difference in atherosclerotic lesion size was found in Ldlr^−/− (low-density lipoprotein receptor null) mice transplanted with bone marrow (BM) cells from Ncr1^iCreR26R^lsl−DTA, Noé, or wild-type mice. Also, no difference was observed in plaque composition in terms of collagen content, macrophage infiltration, or the immune profile, although Noé chimera had more IFN (interferon)-γ–producing NK cells, compared with wild-type mice. Then, we investigated the NK-cell selectivity of anti–asialoganglioside M1 antiserum, which was previously used to conclude the proatherogenicity of NK cells. Anti–asialoganglioside M1 treatment decreased atherosclerosis in both Ldlr^−/− mice transplanted with Ncr1^iCreR26R^lsl−DTA or wild-type bone marrow, indicating that its antiatherogenic effects are unrelated to NK-cell depletion, but to CD8⁺ T and NKT cells. Finally, to determine whether NK cells could contribute to the disease in conditions of pathological NK-cell overactivation, we treated irradiated Ldlr^−/− mice reconstituted with either wild-type or Ncr1^iCreR26R^lsl−DTA bone marrow with the viral mimic polyinosinic:polycytidylic acid and found a significant reduction of plaque size in NK-cell–deficient chimeric mice.

Conclusions: Our findings, using state-of-the-art mouse models, demonstrate that NK cells have no direct effect on the natural development of hypercholesterolemia-induced atherosclerosis, but may play a role when an additional systemic NK-cell overactivation occurs.

基本原理：慢性炎症是动脉粥样硬化发展的核心。涉及先天免疫和适应性免疫。尽管有几项研究评估了自然杀伤 (NK) 细胞在动脉粥样硬化实验动物模型中的功能，但尚不清楚 NK 细胞是否具有保护作用或促动脉粥样硬化效应。先前研究的主要警告之一是缺乏靶向 NK 细胞功能丧失或获得的特异性。

目的：我们使用 2 种选择性遗传方法来研究 NK 细胞在动脉粥样硬化中的作用：（1） NK 细胞耗尽的Ncr1 ^iCre/+ R26 ^{lsl- DTA/+}小鼠和（2） NK 细胞高反应性的Noé小鼠.

方法和结果：在移植了来自Ncr1 ^iCre R26R ^{lsl- DTA}、 Noé或野生型小鼠的骨髓 (BM) 细胞的Ldlr ^-/- （低密度脂蛋白受体缺失）小鼠中发现动脉粥样硬化病变大小没有差异此外，尽管Noé与野生型小鼠相比，嵌合体具有更多产生 IFN（干扰素）-γ 的 NK 细胞。然后，我们研究了抗唾液酸神经节苷脂 M1 抗血清的 NK 细胞选择性，该血清以前被用来总结 NK 细胞的致动脉粥样硬化性。抗唾液酸神经节苷脂 M1 治疗降低了移植Ncr1 ^iCre R26R ^{lsl- DTA}或野生型骨髓的Ldlr ^-/-小鼠的动脉粥样硬化，表明其抗动脉粥样硬化作用与 NK 细胞耗竭无关，但与 CD8 ⁺ T 和 NKT 细胞有关. 最后，为了确定在病理性 NK 细胞过度激活的情况下 NK 细胞是否会导致疾病，我们处理了辐照的 Ldlr ^-/-用野生型或Ncr1 ^iCre R26R ^{lsl - DTA}骨髓和病毒模拟多肌苷：聚胞苷酸重建小鼠，发现 NK 细胞缺陷嵌合小鼠的斑块大小显着减小。

结论：我们使用最先进的小鼠模型的研究结果表明，NK 细胞对高胆固醇血症诱导的动脉粥样硬化的自然发展没有直接影响，但可能在发生额外的全身性 NK 细胞过度激活时发挥作用。