Genetic Depletion or Hyperresponsiveness of Natural Killer Cells Do Not Affect Atherosclerosis Development: Natural Killer Cells and Atherosclerosis

Abstract : Rationale: Chronic inflammation is central in the development of atherosclerosis. Both innate and adaptive immunity are involved. Although several studies have evaluated the functions of NK cells in experimental animal models of atherosclerosis, it is not yet clear whether NK cells behave as protective or pro-atherogenic effectors. One of the main caveats of previous studies was the lack of specificity in targeting loss- or gain-of-function of NK cells. Objective: We used two selective genetic approaches to investigate the role of NK cells in atherosclerosis: 1) Ncr1iCre/+R26lsl-DTA/+ mice in which NK cells were depleted, 2) Noé mice in which NK cells are hyperresponsive. Methods and Results: No difference in atherosclerotic lesion size was found in Ldlr-/- mice transplanted with bone marrow cells from Ncr1iCreR26Rlsl-DTA, Noé or WT 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-γ-producing NK cells, compared with WT mice. Then, we investigated the NK cell selectivity of anti-asialo GM1 anti-serum, which was previously used to conclude to the pro-atherogenicity of NK cells. Anti-asialo GM1 treatment decreased atherosclerosis in both Ldlr-/- mice transplanted with Ncr1iCreR26Rlsl-DTA or WT BM, indicating that its anti-atherogenic 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 WT or Ncr1iCreR26Rlsl-DTA BM with the viral mimic poly(I:C) 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.
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Circulation Research, American Heart Association, 2017, Epub ahead of print. 〈10.1161/CIRCRESAHA.117.311743〉
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Wared Nour-Eldine, Jérémie Joffre, Kazem Zibara, Bruno Esposito, Andreas Giraud, et al.. Genetic Depletion or Hyperresponsiveness of Natural Killer Cells Do Not Affect Atherosclerosis Development: Natural Killer Cells and Atherosclerosis. Circulation Research, American Heart Association, 2017, Epub ahead of print. 〈10.1161/CIRCRESAHA.117.311743〉. 〈inserm-01621409〉

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