HIV Impairs Alveolar Macrophage Function via MicroRNA-144-Induced Suppression of Nrf2

• Type of Material: Article
• Authors: Xian Fan, Emory University; Shannon C Murray, Emory University; Bashar Staitieh, Emory University; Paul Spearman, Emory University; David Guidot, Emory University
• Language: English
• Date: 2021-01-01
• Publisher: ELSEVIER SCIENCE INC
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2020 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.amjms.2020.07.026
• Title of Journal or Parent Work: AMERICAN JOURNAL OF THE MEDICAL SCIENCES
• Volume: 361
• Issue: 1
• Start Page: 90
• End Page: 97
• Grant/Funding Information: Funding for this work was provided by R01HL125042 (DMG), R01AI150475 (PS) and K08 AA024512 (BSS).
• Keywords: ICU SUPPORT; PROGNOSTIC-FACTORS; MICRORNAS; INFECTION; Alveolar macrophage; HIV-1 transgenic rat; Medicine, General & Internal; HOSPITALIZED-PATIENTS; Life Sciences & Biomedicine; Science & Technology; BACTERIAL PNEUMONIA; MIR-144; General & Internal Medicine; PULMONARY COMPLICATIONS; Nrf2; EXPRESSION; MANAGEMENT

Abstract

Background: Despite anti-retroviral therapy, HIV-1 infection increases the risk of pneumonia and causes oxidative stress and defective alveolar macrophage (AM) immune function. We have previously determined that HIV-1 proteins inhibit antioxidant defenses and impair AM phagocytosis by suppressing nuclear factor (erythroid-derived 2)-like 2 (Nrf2). Given its known effects on Nrf2, we hypothesize miR-144 mediates the HIV-1 induced suppression of Nrf2. Methods: Primary AMs isolated from HIV-1 transgenic (HIV-1 Tg) rats and wild type littermates (WT) as well as human monocyte-derived macrophages (MDMs) infected ex vivo with HIV-1 were used. We modulated miR-144 expression using a miR-144 mimic or an inhibitor to assay its effects on Nrf2/ARE activity and AM functions in vitro and in vivo. Results: MiR-144 expression was increased in AMs from HIV-1 Tg rats and in HIV-1-infected human MDMs compared to cells from WT rats and non-infected human MDMs, respectively. Increasing miR-144 with a miR-144 mimic inhibited the expression of Nrf2 and its downstream effectors in WT rat macrophages and consequently impaired their bacterial phagocytic capacity and H2O2 scavenging ability. These effects on Nrf2 expression and AM function were reversed by antagonizing miR-144 ex vivo or in the airways of HIV-1 Tg rats in vivo, but this protection was abrogated by silencing Nrf2 expression. Conclusions: Our results suggest that inhibiting miR-144 or interfering with its deleterious effects on Nrf2 attenuates HIV-1-mediated AM immune dysfunction and improves lung health in individuals with HIV.