Beta-adrenergic receptor mediated inhibitory control of monocyte TNF-α, BOLD response to social exclusion, and peripheral arterial stiffness, in people living with HIV.

Abstract

Background: Growing evidence suggests the experience of social exclusion is associated with increased risk for developing cardiovascular disease (CVD), however the psycho-neuro-immune mechanisms involved in this process remain unclear. Peripheral blood mononuclear cells (PBMCs) play an important role in the etiology of peripheral artery disease. Previous research has uncovered beta-adrenergic receptor inhibitory control (BARIC) of inflammation is blunted in PBMCs from individuals at greater risk for CVD. Furthermore, perceived social threat is shown to upregulate inflammatory processes in PBMCs. Given the excess burden of chronic inflammation and exposure to social ostracism reported in people living with HIV (PWH), the current study utilized an fMRI task paradigm to evaluate whether magnitude of blood oxygen level dependent (BOLD) response to social exclusion is associated with the time course of BARIC in CD16⁺ monocytes in relation to peripheral arterial stiffness.

Methods: BOLD response to the exclusion versus inclusion trials of a modified Cyberball task were measured in 25 PWH (50.8 ± 10.3 yrs) and 19 people living without HIV (PWoH) (52.8 ± 11.9 yrs.). CD16⁺ monocytes, collected 45 min before, 45 min and 90 min after Cyberball, were isolated using magnetic bead separation (StemCell™) and incubated for 18-hr following co-stimulation with lipopolysaccharide (LPS) and the non-selective beta-receptor agonist isoproterenol. BARIC was operationalized as the difference in TNF-α expressed by LPS-stimulated CD16⁺ monocytes without vs. with isoproterenol. A repeated measures ANCOVA assessed whether BOLD response to social exclusion in the subgenual anterior cingulate (sgACC), relates to change in BARIC of TNF-α following the encounter. The interactive effect of HIV+ status and BARIC on peripheral arterial stiffness was evaluated using multiple regression while controlling for age and gender.

Results: Whole-brain analysis revealed sgACC BOLD activation was significantly greater in the sgACC during exclusion compared to inclusion trials surviving FWE small-volume correction (p < 0.05, FWE-SVC). Compared to the middle and highest tercile, individuals within the lowest tercile of sgACC BOLD activation showed an initial BARIC response pre-task followed by a respective decline and recovery in BARIC immediate and 90 minutes post-task (F(1,32) = 5.471, p = .023, η2 = 0.152). Although these neuro-immune associations were not moderated by HIV status, greater BARIC was associated with lower arterial stiffness in PWoH and higher arterial stiffness in PWH (β = -0.89, t = -2.176, p = 0.040).

Conclusion: This study supports the role of sgACC in processing social exclusion and relevance of this biobehavioral response to the time course of beta-adrenergic receptor-mediated inhibitory control of TNF-α expression in intermediate and non-classical monocytes. Further this study provides preliminary evidence of a paradoxical association between greater BARIC of monocyte inflammation and arterial stiffness in PWH who have not yet developed CVD. Replication of these observations is warranted within a larger cohort to determine the contribution of these processes to the development of CVD.