When a Friend Becomes Your Enemy: Natural Killer Cells in Atherosclerosis and Atherosclerosis-Associated Risk Factors

Abstract

Atherosclerosis (ATS), the change in structure and function of arteries with associated lesion formation and altered blood flow, is the leading cause of cardiovascular disease, the number one killer worldwide. Beyond dyslipidemia, chronic inflammation, together with aberrant phenotype and function of cells of both the innate and adaptive immune system, are now recognized as relevant contributors to atherosclerosis onset and progression. While the role of macrophages and T cells in atherosclerosis has been addressed in several studies, Natural Killer cells (NKs) represent a poorly explored immune cell type, that deserves attention, due to NKs' emerging contribution to vascular homeostasis. Furthermore, the possibility to re-polarize the immune system has emerged as a relevant tool to design new therapies, with some succesfull exmples in the field of cancer immunotherapy. Thus, a deeper knowledge of NK cell pathophysiology in the context of atherosclerosis and atherosclerosis-associated risk factors could help developing new preventive and treatment strategies, and decipher the complex scenario/history from "the risk factors for atherosclerosis" Here, we review the current knowledge about NK cell phenotype and activities in atherosclerosis and selected atherosclerosis risk factors, namely type-2 diabetes and obesity, and discuss the related NK-cell oriented environmental signals.

Keywords: atherosclerosis; atherosclerosis-related risk factors; natural killer cells; obesity; type-2 diabetes.

Figure 1

NK cells in atherosclerosis. From the site of atherosclerotic (ATS) plaque formation (A) many cytokines and chemokines are released into the blood, stimulating NK cells migration and entry within the plaque. Infiltrating NK cells can interact, by contact, with other immune cells such as (B) macrophages, that in presence of oxLDL, produce and release IL-12, thus potentiating cytolytic activity of NK via interferon γ (IFNγ) release. OxLDL can also be present as opsonized particles (C) that support dendritic cells (DCs)-NK crosstalk which is also mediated by CD48-2BA interaction and leads to (D) IFNγ release from NKs. IFNγ from NK cells exerts its effect on both (D) smooth muscle cells (SMCs) by inducing their apoptosis and macrophages by promoting M1-like phenotype switch. Furthermore, both (E) macrophages and endothelial cells (ECs) release soluble MICA (sMICA) that upon NKG2D binding on NK cells increase NK killing capability. Within ATS plaque, (F) a subset of NK cells display a hyperactive phenotype/behavior with increased expression of CD49a, CD56, CD69 and CD103 and NK cells (G) modify receptors expression downmodulated CD47 and increasing CD90 marker, leading to IFNγ release.

Figure 2

NK cells in Type 2 diabetes. In humans, circulating NK cells in T2D subjects have been found to increase in number (A) but with decreased expression of both NKp46 and NKG2D activation markers, thus showing a reduced functionality (B). At the molecular level, circulating NK cells in T2D showed an increased mRNA expression of BiP, PDI, and sXBP1, a marker of unfolded protein response (UPR) which in turn is related to ER stress-activated by PERK and IRE1 sensors (C). These mechanisms are related to NKG2D down-modulation in circulating NK cells (C). In addition, NK cells showed an increased general DNA methylation (D). To mimic T2D mice are fed with high fat diet (HFD) (E) and within visceral adipose tissue, NK cells through IFNγ and TNFα release can induce macrophages polarization toward a pro-inflammatory M1-like phenotype thus promoting inflammation (E).

Figure 3

NK cells in obesity. Alteration of NK cells in obese patients includes (A) reduced NK cell frequency, (B) unbalance between anti- and pro-inflammatory behavior of NK cells, and (C) increased release of both perforin and granzymes B, while IFNγ is found both up and down modulated. At the molecular level, NK cells of obese patients showed a (D) increased number of IL6Rα+ cells that correlated with low-grade inflammation markers, (E) decreased expression of NKp46 and NKG2A/CD94, with subsequently reduced cytotoxicity, (F) increased expression CD69 activation marker correlated with increased release of granzyme B, and (G) reduction of CD16 responsible for the reduced ADCC. Finally, the increased circulating level of leptin in obese patients (H) affects NK cells maturation by the inhibition of mTOR signalling in NK cells precursors, resulting in reduced maturation, thus contributing to reduced NK cell frequency.