Immunomodulators targeting MARCO expression improve resistance to postinfluenza bacterial pneumonia

Muzo Wu, John G. Gibbons, Glen M. DeLoid, Alice S. Bedugnis, Rajesh K. Thimmulappa, Shyam Biswa, Lester Kobzik

Research output: Contribution to journalArticle

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 (AMMDMs) 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 AMMDMs 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.

Original languageEnglish (US)
Pages (from-to)L138-L153
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume313
Issue number1
DOIs
StatePublished - 2017

Keywords

  • Akt
  • Bacterial pneumonia
  • Immunomodulators
  • Influenza
  • Interferon-γ
  • Macrophage receptor with collagenous structure
  • Nuclear factor erythroid 2-related factor 2
  • Transcription factor E-box

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Cell Biology
  • Physiology (medical)

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