Baumer-TPW_2023_Dopamine-Monocytes_PMID37251548.xlsx

Social determinants of health (SDoH) include socioeconomic, environmental, and psychological factors thatimpact health. Neighborhood socioeconomic deprivation (NSD) and low individual-level socioeconomic status(SES) are SDoH that associate with incident heart failure, stroke, and cardiovascular mortality, but the underlyingbiological mechanisms are not well understood. Previous research has demonstrated an association betweenNSD, in particular, and key components of the neural-hematopoietic-axis including amygdala activity as amarker of chronic stress, bone marrow activity, and arterial inflammation. Our study further characterizes therole of NSD and SES as potential sources of chronic stress related to downstream immunological factors in thisstress-associated biologic pathway. We investigated how NSD, SES, and catecholamine levels (as proxy forsympathetic nervous system activation) may influence monocytes which are known to play a significant role inatherogenesis. First, in an ex vivo approach, we treated healthy donor monocytes with biobanked serum from acommunity cohort of African Americans at risk for CVD. Subsequently, the treated monocytes were subjected toflow cytometry for characterization of monocyte subsets and receptor expression. We determined that NSD andserum catecholamines (namely dopamine [DA] and norepinephrine [NE]) associated with monocyte C–C chemokinereceptor type 2 (CCR2) expression (p < 0.05), a receptor known to facilitate recruitment of monocytestowards arterial plaques. Additionally, NSD associated with catecholamine levels, especially DA in individuals oflow SES. To further explore the potential role of NSD and the effects of catecholamines on monocytes, monocyteswere treated in vitro with epinephrine [EPI], NE, or DA. Only DA increased CCR2 expression in a dose-dependentmanner (p < 0.01), especially on non-classical monocytes (NCM). Furthermore, linear regression analysis betweenD2-like receptor surface expression and surface CCR2 expression suggested D2-like receptor signaling inNCM. Indicative of D2-signaling, cAMP levels were found to be lower in DA-treated monocytes compared tountreated controls (control 29.78 pmol/ml vs DA 22.97 pmol/ml; p =0.038) and the impact of DA on NCM CCR2expression was abrogated by co-treatment with 8-CPT, a cAMP analog. Furthermore, Filamin A (FLNA), aprominent actin-crosslinking protein, that is known to regulate CCR2 recycling, significantly decreased in DA-treated NCM (p < 0.05), indicating a reduction of CCR2 recycling. Overall, we provide a novel immunologicalmechanism, driven by DA signaling and CCR2, for how NSD may contribute to atherogenesis. Future studiesshould investigate the importance of DA in CVD development and progression in populations disproportionatelyexperiencing chronic stress due to SDoH.