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Immunomodulators targeting MARCO expression improve resistance to postinfluenza bacterial pneumonia
Muzo Wu1, John G Gibbons2, Glen M DeLoid1
1Department of Environmental Health, Harvard T. H. Chan School of Public Health, Harvard University, Boston, Massachusetts.
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 IFNγ to model influenza effects. Activators of Nrf2 (sulforaphane) or Akt (SC79) caused increased MARCO expression and a MARCO-dependent improvement in phagocytosis in IFNγ-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 IFNγ-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.
Insights
Boosting alveolar macrophage receptor with collagenous structure (MARCO) expression enhances defense against secondary bacterial pneumonia after influenza. Targeting Nrf2 or the Akt-TFEB-MARCO pathway improves bacterial clearance and survival.
Area of Science:
- Immunology
- Microbiology
- Cell Biology
Background:
- Downregulation of MARCO on alveolar macrophages increases susceptibility to postinfluenza bacterial pneumonia.
- Postinfluenza bacterial pneumonia is a significant cause of illness and death.
Purpose of the Study:
- To investigate if modulating MARCO expression can enhance host defense and resistance to secondary bacterial pneumonia.
- To identify molecular pathways regulating MARCO recovery after influenza infection.
Main Methods:
- RNAseq analysis to identify MARCO expression patterns and regulatory pathways (Akt, Nrf2, TFEB).
- In vitro studies using human AM-like macrophages treated with IFNγ, Nrf2 activator (sulforaphane), or Akt activator (SC79).
- In vivo studies in mice with postinfluenza pneumococcal pneumonia; TFEB knockdown experiments.
Main Results:
- MARCO expression significantly increased between days 9-11 post-influenza, with roles for Akt and Nrf2.
- Nrf2 and Akt activators increased MARCO expression and phagocytosis in IFNγ-treated macrophages.
- Activation of Akt increased MARCO expression via TFEB, improving survival in mice with secondary pneumonia.
Conclusions:
- Targeting Nrf2 signaling or the Akt-TFEB-MARCO pathway can increase MARCO expression.
- Modulating MARCO offers a promising strategy to improve bacterial clearance and survival in postinfluenza bacterial pneumonia.