LDL Associates with Decreasing NKp46 Expression on NK cells as a Potential Contributor to Increased Cardiovascular Disease Risk

Background: Dyslipidemia disproportionately affects African American (AA) women and contributes to disparate cardiovascular disease (CVD) outcomes. We previously showed that Natural Killer (NK) cells are functionally impaired by hyperlipidemia, particularly LDL, in a DUSP1 -dependent mechanism. However, the impact of dyslipidemia on NK cell activity-regulating receptor expression (e.g., NKp46) is not completely understood. Therefore, we sought to elucidate the potential impact of LDL on NK cell NKp46 expression in AA women. Methods: NK cell-NKp46 expression was measured by flow cytometry in fresh blood samples from the Step It Up: Physical Activity Intervention participants (n=154). We used multivariable regression to examine associations between plasma lipid profile (LDL, HDL, triglycerides, and total cholesterol) and NK-NKp46 expression. Subsequently, we performed in vitro experiments with freshly isolated naïve NK cells with and without overnight LDL treatment. We used flow cytometry to determine a potential causal impact of LDL on NKp46 expression on NK cells. Results: All Step It Up study participants were AA women (mean age 57 years, mean BMI 36.1 kg/m^2, at intermediate risk for CVD). In the unadjusted model, LDL associated negatively with NKp46 expression on all NK cells (b=-0.18, p=0.03), while no significant associations were found with HDL, triglycerides, or total cholesterol levels. These observed associations persisted after adjustment for BMI and ASCVD 10-year risk (b= -0.17, p=0.04). When focusing on NK cell subsets, LDL trended to significance with NKp46 on cytotoxic NK cells (p=0.08), while no associations were seen with NKp46 expression on proliferative NK cells (p=0.47). For NK cells treated overnight with LDL, NKp46 expression on all NK cells was reduced by 6.78% (p=0.008), mainly driven by a 6.37% reduction on the cytotoxic NK cell subset (p<0.001). The proliferative NK cell subset showed no significant decrease in NKp46 expression levels (p=0.56) compared to vehicle-treated controls (Figure). Conclusion: Our data demonstrate that an LDL-induced reduction in NKp46 expression on NK cells could present an additional pathway by which hyperlipidemia impairs NK cell function, potentially accelerating CVD development and progression in AA women with hyperlipidemia and CVD.