MARCO regulates early inflammatory responses against influenza: a useful macrophage function with adverse outcome

Am J Respir Cell Mol Biol. 2011 Nov;45(5):1036-44. doi: 10.1165/rcmb.2010-0349OC. Epub 2011 May 11.

Abstract

Lung macrophages use the scavenger receptor MARCO to bind and ingest bacteria, particulate matter, and post cellular debris. We investigated the role of MARCO in influenza A virus (IAV) pneumonia. In contrast to higher susceptibility to bacterial infection, MARCO(-/-) mice had lower morbidity and mortality from influenza pneumonia than wild-type (WT) mice. The early course of influenza in MARCO(-/-) lungs was marked by an enhanced but transient neutrophilic inflammatory response and significantly lower viral replication compared with the WT mice. At later time points, no significant differences in lung histopathology or absolute numbers of T lymphocyte influx were evident. Uptake of IAV by WT and MARCO(-/-) bronchoalveolar lavage macrophages in vitro was similar. By LPS coadministration, we demonstrated that rapid neutrophil and monocyte influx during the onset of influenza suppressed viral replication, indicating a protective role of early inflammation. We hypothesized that the presence of increased basal proinflammatory post cellular debris in the absence of scavenging function lowered the inflammatory response threshold to IAV in MARCO(-/-) mice. Indeed, MARCO(-/-) mice showed increased accumulation of proinflammatory oxidized lipoproteins in the bronchoalveolar lavage early in the infection process, which are the potential mediators of the observed enhanced inflammation. These results indicate that MARCO suppresses a protective early inflammatory response to influenza, which modulates viral clearance and delays recovery.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Bronchoalveolar Lavage Fluid / chemistry
  • Influenza A virus / metabolism
  • Influenza A virus / physiology
  • Lipopolysaccharides / toxicity
  • Lipoproteins / analysis
  • Lipoproteins / metabolism
  • Macrophages, Alveolar / metabolism*
  • Macrophages, Alveolar / pathology
  • Macrophages, Alveolar / virology
  • Male
  • Mice
  • Neutrophils / metabolism
  • Neutrophils / pathology
  • Neutrophils / virology
  • Orthomyxoviridae Infections / metabolism*
  • Orthomyxoviridae Infections / pathology
  • Pneumonia, Viral / metabolism*
  • Pneumonia, Viral / pathology
  • Pneumonia, Viral / virology
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / metabolism*
  • Virus Replication

Substances

  • Lipopolysaccharides
  • Lipoproteins
  • Marco protein, mouse
  • Receptors, Immunologic