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

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) Noe 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(iCre)R26R(lsl-DTA), Noe, or wild-type mice. Also, no difference was observed in plaque composition in terms of collagen content, macrophage infiltration, or the immune profile, although Noe chimera had more IFN (interferon)-gamma-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(iCre)R26R(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(iCre)R26R(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.