Abstract Body: Background: Obesity and hyperlipidemia disproportionally affect African American (AA) women due to lifelong exposure to adverse social determinants of health (SDoH), leading to greater cardiovascular disease (CVD) risk. CVD risk factors and adverse SDoH are linked to poor immune health, particularly dysfunctional Natural killer (NK) cells. We recently showed that DUSP1, an NFkB regulator and glucocorticoid receptor gene, is a regulator of NK cell function in obesity and hyperlipidemia. NK cells express activity-regulating receptors, like NKG2D, an important receptor for homeostatic NK cell function. NK cell NKG2D inhibition in mouse models of atherosclerosis appears protective via its direct reduction in macrophage lipid uptake. We investigated relationships between DUSP1, NKG2D gene expression, and NKG2D receptor expression in community-based intervention cohort at risk for CVD.
Methods: DUSP1 was overexpressed (oe) in NK-92 cells utilizing the Sleeping Beauty technique. DUSP1oe NK-92 cells underwent RNA sequencing to determine DUSP1-driven changes in NKG2D gene expression. NK cell-NKG2D expression was measured by flow cytometry in fresh blood samples of the Step It Up Physical Activity Intervention cohort (n=132). We used multivariable regression to examine associations between perceived neighborhood conditions (perceived disorder, violence, safety, and social cohesion measured by validated surveys; higher score=more favorable perceptions) and NK-NKG2D expression.
Results: Pathway analysis of the RNA sequencing revealed dysregulation of inflammatory processes and lipid homeostasis. DUSP1oe NK-92 cells showed increased gene expression of NKG2D (1.73fold, p=0.02). Multivariable regression showed that more favorable perceived neighborhood violence associated with lower NK-NKG2D expression in study participants after adjusting for BMI and ASCVD 10-year risk (b=-0.20, p=0.02). This association remained significant after adjustment for income (b=-0.19, p=0.04). Perceived disorder, safety, and social cohesion were not associated with NK-NKG2D expression.
Conclusions: DUSP1oe NK cells have increased NKG2D expression, a potential marker of atherogenesis connecting NK cells to macrophage function. Among AA women with CVD risk, perceived neighborhood violence associated with NK-NKG2D expression. Future studies should determine the potential role of NKG2D as a CVD risk marker or target for interventions to reduce CVD risk in populations impacted by adverse SDoH.