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Published on: February 22, 2020
Genetic Depletion or Hyperresponsiveness of Natural Killer Cells Do Not Affect Atherosclerosis Development
Wared Nour-Eldine1, Jérémie Joffre1, Kazem Zibara1
1From the Institut National de la Santé et de la Recherche Médicale (Inserm), Unit 970, Paris-Cardiovascular Research Center, Université Paris-Descartes, France (W.N.-E., J.J., B.E., A.G., L.Z., J.V., P.B., H.A.-O., Z.M., A.T.); ER045, PRASE (W.N.-E., K.Z.) and Biology Department, Faculty of Sciences-I (K.Z.), Lebanese University, Beirut, Lebanon; Department of Anatomopathology, Hôpital Européen Georges Pompidou, Assistance Publique-Hopitaux de Paris, France (M.T., P.B.); Centre d'Immunologie de Marseille-Luminy, Aix Marseille University, CNRS, INSERM, France (E.V., S.U.); and Division of Cardiovascular Medicine, Department of Medicine, University of Cambridge, United Kingdom (Z.M.).
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) Ncr1iCre/+R26lsl-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 Ncr1iCreR26Rlsl-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 Ncr1iCreR26Rlsl-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 Ncr1iCreR26Rlsl-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.
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