Natural Killer Cells in the Orchestration of Chronic Inflammatory Diseases

Figure 5

Proatherosclerosis role of natural killer cells. NK ability to induce atherosclerosis has been reported in several murine models and in humans. Several cytokines and chemokines within atherosclerotic lesions are supposed to promote NK recruitment towards atherosclerotic plaque, including monocyte chemoattractant protein-1 (MCP-1), fractalkine (CX3CL1), IL-15, IL-12, IL-18, and IFN-α that on one hand enhance NK cell migration and on the other hand induce NK activation resulting in an increased IFN-γ release. Moreover, these cytokines as far as oxidized LDL also promote the NK crosstalk with other immune cells, that is, dendritic cells and macrophages. DCs activated NKs by releasing IL-12 that in turn induce the production of IFN-γ by NKs that are able to lyse smooth muscle cells. In addition, IFN-γ released NK cells that in turn promote metalloproteinases (MMPs) secretion from cDCs and MΦ (a). In a chimeric atherosclerosis-susceptible low-density lipoprotein (LDL) receptor null (ldl-r−/−) mouse model, characterized by the impairment of NK cell functionality through the expression of a transgene encoding for Ly49A, it has been demonstrated that even if no difference in either serum total cholesterol concentrations or lipoprotein cholesterol distribution was observed between the two groups of mice, in Ly49A transgenic group, the deficiency of functional NK cells significantly reduced the size of atherosclerosis by 70% in cross-sectional analysis of the aortic root and by 38% in the intimal surface of the aortic arch (b). The administration of anti-Asialo-GM1 antibodies in ApoE(−/−) mice induces a NK cells depletion leading to an attenuation of atherosclerosis (c). The transfer of NK cells isolated from murine spleen into ApoE(−/−)Rag2(−/−)IL2rg(−/−) induces an enhancement of atherosclerosis (d).

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