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Role of Monocyte-Derived MicroRNA106b?25 in Resilience to Social Stress.

ABSTRACT: BACKGROUND:Clinical studies suggest that heightened peripheral inflammation contributes to the pathogenesis of stress-related disorders, including major depressive disorder. However, the molecular mechanisms within peripheral immune cells that mediate enhanced stress vulnerability are not well known. Because microRNAs (miRs) are important regulators of immune response, we sought to examine their role in mediating inflammatory and behavioral responses to repeated social defeat stress (RSDS), a mouse model of stress vulnerability that produces susceptible and resilient phenotypes. METHODS:We isolated Ly6chigh monocytes via fluorescence-activated cell sorting in the blood of susceptible and resilient mice following RSDS and profiled miR expression via quantitative real-time polymerase chain reaction. Bone marrow chimeric mice were generated to confirm a causal role of the miR-106b?25 cluster in bone marrow-derived leukocytes in mediating stress resilience versus susceptibility. RESULTS:We found that RSDS produces an increase in circulating Ly6chigh inflammatory monocytes in both susceptible and resilient mice. We next investigated whether intrinsic leukocyte posttranscriptional mechanisms contribute to individual differences in stress response and the resilient phenotype. Of the miRs profiled in our panel, eight were significantly regulated by RSDS within Ly6chigh monocytes, including miR-25-3p, a member of the miR-106b?25 cluster. Selective knockout of the miR-106b?25 cluster in peripheral leukocytes promoted behavioral resilience to RSDS. CONCLUSIONS:Our results identify the miR-106b?25 cluster as a key regulator of stress-induced inflammation and depression that may represent a novel therapeutic target for drug development.

SUBMITTER: Pfau ML

PROVIDER: S-EPMC6717005 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Role of Monocyte-Derived MicroRNA106b∼25 in Resilience to Social Stress.

Pfau Madeline L ML Menard Caroline C Cathomas Flurin F Desland Fiona F Kana Veronika V Chan Kenny L KL Shimo Yusuke Y LeClair Katherine K Flanigan Meghan E ME Aleyasin Hossein H Walker Deena M DM Bouchard Sylvain S Mack Matthias M Hodes Georgia E GE Merad Miriam M MM Russo Scott J SJ

Biological psychiatry 20190329 6

<h4>Background</h4>Clinical studies suggest that heightened peripheral inflammation contributes to the pathogenesis of stress-related disorders, including major depressive disorder. However, the molecular mechanisms within peripheral immune cells that mediate enhanced stress vulnerability are not well known. Because microRNAs (miRs) are important regulators of immune response, we sought to examine their role in mediating inflammatory and behavioral responses to repeated social defeat stress (RSD ...[more]

PMID: 31101319

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Project description:Background:Alcohol consumption is considered to be a major health problem among people living with HIV/AIDS. Our previous reports have shown that ethanol reduced intracellular concentrations of antiretroviral drugs elvitegravir and darunavir in the HIV-1-infected U1 cell line. Ethanol also increased HIV-1 replication despite the presence of elvitegravir. Our previous finding has also shown that the levels of cytochrome P450 enzyme 2E1 (CYP2E1) and oxidative stress in blood monocytes were induced, while the concentration of alcohol in the plasma was reduced in HIV-1-infected alcohol users compared to uninfected alcohol users. However, the role of CYP2E1 in ethanol-enhanced oxidative stress and HIV-1 replication is still unclear. Methods:This study examined the chronic effects (14 days) of ethanol on HIV viral load, oxidative DNA damage, expression of CYP2E1, expression of antioxidant enzymes (AOEs), expression of reactive oxygen species (ROS) in human monocyte-derived macrophages (MDM). Further, to evaluate the role of CYP2E1 in mediating ethanol-induced viral replication, CYP2E1 siRNA and CYP2E1 selective inhibitor were used in the HIV-1-infected U1 cell line following ethanol treatment. Results:Chronic ethanol exposure demonstrated an increase in oxidative DNA damage and CYP2E1 expression in both non-infected and HIV-1-infected MDM. Our results showed that ethanol chronic exposure increased HIV-1 replication by ~3-fold in HIV-1-infected MDM. This ethanol-enhanced HIV-1 replication was associated with an increased oxidative DNA damage, an increased expression of CYP2E1, and a decreased expression of antioxidant enzyme PRDX6. In HIV-1-infected U1 cell line, we observed a decreased viral replication (~30%) and a decreased DNA damage (~100%) after repression of CYP2E1 by siRNA, upon ethanol exposure. We also observed a decreased viral replication (~25%) after inhibition of CYP2E1 by using selective CYP2E1 inhibitor. Conclusions:The data suggest that chronic ethanol exposure increases HIV-1 replication in MDM, at least in part, through CYP2E1-mediated oxidative stress. These results are clinically relevant to potentially find effective treatment strategies for HIV-1-infected alcohol users.

Dataset Information

Role of Monocyte-Derived MicroRNA106b?25 in Resilience to Social Stress.

Publications

Role of Monocyte-Derived MicroRNA106b∼25 in Resilience to Social Stress.

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