Immunomodulators Targeting MARCO Expression Improve Resistance to Post-influenza Bacterial Pneumonia.

American journal of physiology. Lung cellular and molecular physiology

PubMedID: 28408365

Wu M, Gibbons JG, Deloid GM, Bedugnis AS, Thimmulappa RK, Biswal S, Kobzik L. Immunomodulators Targeting MARCO Expression Improve Resistance to Post-influenza Bacterial Pneumonia. Am J Physiol Lung Cell Mol Physiol. 2017;ajplung.00075.2017.
Down-regulation of the alveolar macrophage (AM) macrophage receptor with collagenous structure (MARCO) leads to susceptibility to post-influenza 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 of 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 post-influenza 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 Akt-TFEB-MARCO pathway are promising strategies to improve bacterial clearance and survival in post-influenza bacterial pneumonia.