Senescent Phenotype Induced by p90RSK-NRF2 Signaling Sensitizes Monocytes and Macrophages to Oxidative Stress in HIV-Positive Individuals

Abstract

Background: The incidence of cardiovascular disease (CVD) is higher in HIV + patients than it is in the average population, and combination antiretroviral therapy (cART) is a recognized risk factor for CVD. However, the molecular mechanisms that link cART and CVD are currently unknown. Our study explores the role of the activation of p90RSK, a reactive oxygen species (ROS)-sensitive kinase, in engendering senescent phenotype in macrophages and accelerating atherogenesis in patients undergoing cART. Methods: Peripheral whole blood from cART-treated HIV + individuals and non-treated HIV − individuals was treated with H 2 O 2 (200 μM) for 4 minutes, and p90RSK activity in CD14 + monocytes was measured. Plaque formation in the carotids were also analyzed in these individuals. Macrophage senescence was determined by evaluating their efferocytotic ability, antioxidation-related molecule expression, telomere length, and inflammatory gene expression. The involvement of p90RSK-NRF2 signaling in cART-induced senescence was assessed by p90RSK specific inhibitor (FMK-MEA) or dominant negative p90RSK (DN-p90RSK), and NRF2 activator (NRF2A). Further, the severity of atherosclerosis was determined in myeloid cell-specific wild type and DN-p90RSK transgenic mice. Results: Monocytes from HIV + patients exhibited higher levels of p90RSK activity and were also more sensitive to ROS than monocytes from HIV − individuals. A multiple linear regression analysis involving cART, Reynolds CV risk score, and basal p90RSK activity revealed that cART and basal p90RSK activity were the two significant determinants of plaque formation. Many of the antiretroviral drugs individually activated p90RSK, which simultaneously triggered all components of the macrophage senescent phenotype. cART inhibited antioxidant response element reporter activity via ERK5 S496 phosphorylation. NRF2A reversed the H 2 O 2-induced over-activation of p90RSK in cART-treated macrophages by countering the induction of senescent phenotype. Lastly, the data obtained from our gain-or loss-of-function mice conclusively showed the crucial role of p90RSK in inducing senescent phenotype in macrophages and atherogenesis. Conclusions: cART increased monocyte/macrophage sensitivity to ROS in HIV + individuals by suppressing NRF2-ARE activity via p90RSK-mediated ERK5 S496 phosphorylation, which coordinately elicited senescent phenotypes and pro-inflammatory responses. As such, our report underscores the importance of p90RSK regulation in monocytes/macrophages as a viable biomarker and therapeutic target for preventing CVD, especially in HIV + patients treated with cART.

The Ser/Thr kinase p90RSK promotes kidney fibrosis by modulating fibroblast–epithelial crosstalk

“…recent findings that p90RSK is involved in the pathogenesis of atherosclerosis of various causes (11,29,30). In the present study, we found that the abundance of total p90RSK was little changed during progressive CKD.…”

SARS-CoV-2 Mediated Endothelial Dysfunction: The Potential Role of Chronic Oxidative Stress

“…The aforementioned formation of ONOO – also occurs within the mitochondrial matrix through mitochondrial O 2 – , which further damages the ETC ( Pacher et al, 2007 ). The activation of p90RSK by mtROS and subsequent ERK5 S496 phosphorylation may further exacerbate oxidative stress, as evidenced by increased levels of redox-sensitive p90RSK enzymatic activity, by inhibiting transcription of the antioxidant nuclear factor erythroid 2-related factor 2 ( Singh et al, 2019 ). mtROS-mediated NLRP3 inflammasome activation and redox-sensitive kinase cascades produce inflammatory cytokines like IL-1β and TNF, which can activate NADPH oxidase and further perpetuate oxidative stress ( Figure 1 ; Kaur et al, 2004 ; Yang et al, 2007 ).…”

“…This is particularly relevant, as we have discussed how SARS-CoV-2 may induce continuous excess ROS production and p90RSK-mediated ERK5 S496 phosphorylation ( Vu et al, 2018 ). Previous research indicates that HIV cART treatment increases long-term risk for cardiovascular disease by inducing p90RSK-mediated SASP, so SARS-CoV-2 infection may have a similar effect in inducing chronic senescence and inflammation in ECs ( Singh et al, 2019 ). This further exacerbates the oxidative stress-mediated induction of SASP, production of inflammatory cytokines, and subsequent dysfunction in ECs.…”

Biomarkers of Activation and Inflammation to Track Disparity in Chronological and Physiological Age of People Living With HIV on Combination Antiretroviral Therapy

“…cART is more effective at limiting plasma sCD163 levels, though relative to uninfected individuals, there is discrepancy on whether levels are comparable or higher ( 42 , 112 , 113 ). Further, CD14+ monocytes were shown to exhibit increased p90RSK activity, which is a reactive oxygen species-sensitive kinase, in the presence of cART which suppresses NRF2-ARE transcriptional activity eliciting a senescent phenotype along with pro-inflammatory responses ( 114 ). In another study, HIV cell-associated DNA (in CSF and blood) and sCD163 (in CSF) were significantly correlated with cognitive impairment, particularly executive function, in older adults, but not in young adults ( 115 ).…”