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.
Key Indexing Terms
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Article info
Publication history
Published online: July 20, 2020
Accepted:
July 17,
2020
Received:
January 17,
2020
Footnotes
The authors declare no conflicts of interests.
Funding for this work was provided by R01HL125042 (DMG), R01AI150475 (PS) and K08 AA024512 (BSS).
Identification
Copyright
© 2020 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.
