Lp(a) impairs NK cell function potentially contributes to impaired immunity and increased cardiovascular disease risk
Y Baumer, A Saurabh, L Mendelsohn, T Powell-WileyAbstract
Background/Introduction
Natural killer (NK) cells are increasingly recognized as important contributors to cardiovascular disease (CVD) and adverse cardiometabolic outcomes. Yet, the mechanisms driving NK cell dysfunction in populations at highest CVD risk remain poorly understood. Lipoprotein (a) has gained attention as an independent risk factor for CVD, with potent pro-atherogenic and pro-inflammatory properties. Notably, circulating Lp(a) levels are up to threefold higher in African Americans, a population that also experiences the highest burden of CVD and disproportionate exposure to chronic psychosocial stressors compared to other US populations.
Purpose
The purpose of this study was to determine and characterize the impact of Lp(a) on NK cells.
Methods
NK cell function was determined using a flow cytometry-based degranulation assay that measures receptor-mediated activation of NK cells after exposure to K562 target cells. This assay was performed utilizing freshly isolated primary human NK cells. For further in vitro analysis, NK cells were incubated with 20mg/dl Lp(a) overnight and subsequently subjected to RNA sequencing and proteomics analysis, as well as flow cytometry-based techniques to measure cellular and mitochondrial reactive oxygen species (ROS) formation as well as mitochondrial membrane potential. Release of mitochondrial DNA was detected by RT-qPCR, while inflammasome activation was determined using Western Blotting. The secretion of cytokines, including IFNg, TNFa, IL-1b, and IL-18, was measured using ELISA.
Results
In a cohort of 24 African American women (mean age 55 years) at intermediate CVD risk (mean ASCVD 10-year risk score=7.1), we observed a significant association between higher Lp(a) levels and lower NK cell degranulation (b=-0.42, p=0.04 after adjustment for BMI and ASCVD risk score). To investigate the underlying mechanisms, NK cells were exposed to Lp(a) in vitro. Lp(a) treated NK cells displayed decreased killing and degranulation capacity as well as cytokine production and secretion when exposed to K562 target cells. Transcriptomic and proteomics analysis revealed significant suppression of mitochondrial and energy metabolism–related signaling pathways. Consistent with these findings, transmission electron microscopy demonstrated Lp(a)-induced mitochondrial abnormalities, accompanied by increased cellular (5-fold) and mitochondrial (2-fold) ROS, and a 29% reduced mitochondrial membrane potential. An Lp(a)-induced mitochondrial DNA release was detected; however, this release did not result in NLRP3 or cGAS/Sting inflammasome activation.
Conclusion
We identify Lp(a) as a direct modulator of NK cell function and suggest that Lp(a)-induced mitochondrial dysfunction is a key mechanism underlying NK cell impairment. This pathway may represent one of the multifaceted biological mechanisms contributing to cardiovascular health disparities observed in African American populations.