HIV Impairs Alveolar Macrophage Function via MicroRNA-144-Induced Suppression of Nrf2.
HIV Impairs Alveolar Macrophage Function via MicroRNA-144-Induced Suppression of Nrf2.
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DOI：
10.1016/j.amjms.2020.07.026
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Guidot DM
中科院分区：
文献类型：
--
作者：
Fan X;Murray SC;Staitieh BS;Spearman P;Guidot DM
尽管有抗逆转录病毒治疗，HIV-1感染增加了肺炎的风险，并导致氧化应激和肺泡巨噬细胞（AM）免疫功能缺陷。我们先前已经确定HIV-1蛋白通过抑制核因子（红细胞衍生2）样2（Nrf 2）抑制抗氧化防御和损害AM吞噬作用。鉴于其对Nrf 2的已知作用，我们假设miR-144介导HIV-1诱导的Nrf 2抑制。使用了从HIV-1转基因（HIV-1 Tg）大鼠和野生型同窝仔（WT）以及离体感染HIV-1的人单核细胞衍生巨噬细胞（MDM）中分离的原代AM。我们使用miR-144模拟物或抑制剂调节miR-144表达，以测定其对体外和体内Nrf 2/ARE活性和AM功能的影响。与来自WT大鼠和未感染的人MDM的细胞相比，来自HIV-1 Tg大鼠的AM和HIV-1感染的人MDM中的miR-144表达分别增加。用miR-144模拟物增加miR-144抑制WT大鼠巨噬细胞中Nrf 2及其下游效应物的表达，从而损害其细菌吞噬能力和H2 O2清除能力。这些对Nrf 2表达和AM功能的影响可通过体外拮抗miR-144或体内拮抗HIV-1 Tg大鼠气道中的miR-144来逆转，但这种保护作用可通过沉默Nrf 2表达来消除。我们的研究结果表明，抑制miR-144或干扰其对Nrf 2的有害作用可减弱HIV-1介导的AM免疫功能障碍，并改善HIV感染者的肺部健康。
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. 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. 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. 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.
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DOI：
10.1164/ajrccm.162.2.9912058
发表时间：
2000-08-01
影响因子：
24.7
作者：
Morris, AM;Huang, L;Stansell, JD
通讯作者：
Stansell, JD
影响因子：
3.7
作者：
Narasimhan M;Patel D;Vedpathak D;Rathinam M;Henderson G;Mahimainathan L
通讯作者：
Mahimainathan L
影响因子：
2.2
作者：
Lassiter, Coy;Fan, Xian;Joshi, Pratibha C;Jacob, Barbara A;Sutliff, Roy L;Jones, Dean P;Koval, Michael;Guidot, David M
通讯作者：
Guidot, David M
影响因子：
7.4
作者：
Guo Y;Yu S;Zhang C;Kong AN
通讯作者：
Kong AN
影响因子：
9.6
作者：
Crothers, Kristina;Butt, Adeel A.;Justice, Amy C.
通讯作者：
Justice, Amy C.