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The Metabolic Woes of the Alveolar Macrophage in HIV
Author(s) -
Yeligar Samantha M.,
Auld Sara C.,
Staitieh Bashar S.
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.01828
Subject(s) - bronchoalveolar lavage , oxidative stress , alveolar macrophage , immune system , immunology , nox4 , nox1 , biology , mitochondrion , nadph oxidase , macrophage , microbiology and biotechnology , medicine , lung , endocrinology , biochemistry , in vitro
Objective Despite anti‐retroviral therapy, people with human immunodeficiency virus (HIV) are still at high risk for respiratory infections and non‐infectious pulmonary diseases. Alveolar macrophages (AM), which act as a viral reservoir, are critical immune effectors in the lung that phagocytize and clear pathogens. We have previously shown that oxidative stress impairs AM phagocytic function. Therefore, we hypothesized that HIV causes AM immune dysfunction by increasing oxidative stress by (1) up‐regulating NADPH oxidases (Noxes), which are the primary sources of cellular oxidative stress in the AM, and (2) causing mitochondrial derangements and consequent increases in mitochondria‐derived oxidative stress. Methods AM were isolated from the bronchoalveolar lavage fluid of HIV transgenic rats that express the HIV proteins, trans‐activator of transcription and glycoprotein‐120, or littermate control rats. AM were also isolated from the bronchoalveolar lavage fluid of people with HIV or otherwise healthy control subjects. mRNA and protein levels of Noxes were assessed by qRT‐PCR and cytoimmunostaining, respectively. Mitochondrial oxygen consumption rate and bioenergetics were measured by Cell Mito Stress Test assay using an extracellular flux analyzer. AM phagocytosis was evaluated by pHrodo‐labelled S. aureus internalization. Results Compared with controls, AM from HIV transgenic rats and people with HIV exhibited: (a) increased mRNA levels of Nox1, Nox2, and Nox4; (b) increased protein expression of Nox1, Nox2, and Nox4; (c) decreased mitochondrial respiration and bioenergetics; and (d) decreased AM phagocytic function. Conclusions HIV increases cellular sources of oxidative stress via upregulation of Noxes and mitochondrial sources of oxidative stress via derangements in mitochondrial function, which may contribute to impaired AM phagocytosis. Therapeutic targeting of oxidative stress pathways could provide a novel approach to improving lung immune defense in people with HIV. Support or Funding Information Research Funding Sources : NIAAA R00AA021803 and R01AA026086 to SMY, NIAID K23AI134182 to SCA, and NIAAA K08AA024512 to BSS.