Baumer-TPW_2023_Dopamine-Monocytes_PMID37251548.xlsx

Social determinants of health (SDoH) include socioeconomic, environmental, and psychological factors that
impact 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 underlying
biological mechanisms are not well understood. Previous research has demonstrated an association between
NSD, in particular, and key components of the neural-hematopoietic-axis including amygdala activity as a
marker of chronic stress, bone marrow activity, and arterial inflammation. Our study further characterizes the
role of NSD and SES as potential sources of chronic stress related to downstream immunological factors in this
stress-associated biologic pathway. We investigated how NSD, SES, and catecholamine levels (as proxy for
sympathetic nervous system activation) may influence monocytes which are known to play a significant role in
atherogenesis. First, in an ex vivo approach, we treated healthy donor monocytes with biobanked serum from a
community cohort of African Americans at risk for CVD. Subsequently, the treated monocytes were subjected to
flow cytometry for characterization of monocyte subsets and receptor expression. We determined that NSD and
serum catecholamines (namely dopamine [DA] and norepinephrine [NE]) associated with monocyte C–C chemokine
receptor type 2 (CCR2) expression (p < 0.05), a receptor known to facilitate recruitment of monocytes
towards arterial plaques. Additionally, NSD associated with catecholamine levels, especially DA in individuals of
low SES. To further explore the potential role of NSD and the effects of catecholamines on monocytes, monocytes
were treated in vitro with epinephrine [EPI], NE, or DA. Only DA increased CCR2 expression in a dose-dependent
manner (p < 0.01), especially on non-classical monocytes (NCM). Furthermore, linear regression analysis between
D2-like receptor surface expression and surface CCR2 expression suggested D2-like receptor signaling in
NCM. Indicative of D2-signaling, cAMP levels were found to be lower in DA-treated monocytes compared to
untreated controls (control 29.78 pmol/ml vs DA 22.97 pmol/ml; p =0.038) and the impact of DA on NCM CCR2
expression was abrogated by co-treatment with 8-CPT, a cAMP analog. Furthermore, Filamin A (FLNA), a
prominent 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 immunological
mechanism, driven by DA signaling and CCR2, for how NSD may contribute to atherogenesis. Future studies
should investigate the importance of DA in CVD development and progression in populations disproportionately
experiencing chronic stress due to SDoH.