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Immunomodulators targeting MARCO expression improve resistance to postinfluenza bacterial pneumonia.


ABSTRACT: Downregulation of the alveolar macrophage (AM) receptor with collagenous structure (MARCO) leads to susceptibility to postinfluenza bacterial pneumonia, a major cause of morbidity and mortality. We sought to determine whether immunomodulation of MARCO could improve host defense and resistance to secondary bacterial pneumonia. RNAseq analysis identified a striking increase in MARCO expression between days 9 and 11 after influenza infection and indicated important roles for Akt and Nrf2 in MARCO recovery. In vitro, primary human AM-like monocyte-derived macrophages (AM-MDMs) and THP-1 macrophages were treated with IFN? to model influenza effects. Activators of Nrf2 (sulforaphane) or Akt (SC79) caused increased MARCO expression and a MARCO-dependent improvement in phagocytosis in IFN?-treated cells and improved survival in mice with postinfluenza pneumococcal pneumonia. Transcription factor analysis also indicated a role for transcription factor E-box (TFEB) in MARCO recovery. Overexpression of TFEB in THP-1 cells led to marked increases in MARCO. The ability of Akt activation to increase MARCO expression in IFN?-treated AM-MDMs was abrogated in TFEB-knockdown cells, indicating Akt increases MARCO expression through TFEB. Increasing MARCO expression by targeting Nrf2 signaling or the Akt-TFEB-MARCO pathway are promising strategies to improve bacterial clearance and survival in postinfluenza bacterial pneumonia.

SUBMITTER: Wu M 

PROVIDER: S-EPMC5538876 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Immunomodulators targeting MARCO expression improve resistance to postinfluenza bacterial pneumonia.

Wu Muzo M   Gibbons John G JG   DeLoid Glen M GM   Bedugnis Alice S AS   Thimmulappa Rajesh K RK   Biswal Shyam S   Kobzik Lester L  

American journal of physiology. Lung cellular and molecular physiology 20170413 1


Downregulation of the alveolar macrophage (AM) receptor with collagenous structure (MARCO) leads to susceptibility to postinfluenza bacterial pneumonia, a major cause of morbidity and mortality. We sought to determine whether immunomodulation of MARCO could improve host defense and resistance to secondary bacterial pneumonia. RNAseq analysis identified a striking increase in MARCO expression between <i>days 9</i> and <i>11</i> after influenza infection and indicated important roles for Akt and N  ...[more]

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