Neonatal Pulmonary Macrophage Depletion Coupled to Defective Mucus Clearance Increases Susceptibility to Pneumonia and Alters Pulmonary Immune Responses

Am J Respir Cell Mol Biol. 2016 Feb;54(2):210-21. doi: 10.1165/rcmb.2014-0111OC.

Abstract

Resident immune cells (e.g., macrophages [MΦs]) and airway mucus clearance both contribute to a healthy lung environment. To investigate interactions between pulmonary MΦ function and defective mucus clearance, a genetic model of lysozyme M (LysM) promoter-mediated MΦ depletion was generated, characterized, and crossed with the sodium channel β subunit transgenic (Scnn1b-Tg) mouse model of defective mucus clearance. Diphtheria toxin A-mediated depletion of LysM(+) pulmonary MΦs in wild-type mice with normal mucus clearance resulted in lethal pneumonia in 24% of neonates. The pneumonias were dominated by Pasteurella pneumotropica and accompanied by emaciation, neutrophilic inflammation, and elevated Th1 cytokines. The incidence of emaciation and pneumonia reached 51% when LysM(+) MΦ depletion was superimposed on the airway mucus clearance defect of Scnn1b-Tg mice. In LysM(+) MΦ-depleted Scnn1b-Tg mice, pneumonias were associated with a broader spectrum of bacterial species and a significant reduction in airway mucus plugging. Bacterial burden (CFUs) was comparable between Scnn1b-Tg and nonpneumonic LysM(+) MΦ-depleted Scnn1b-Tg mice. However, the nonpneumonic LysM(+) MΦ-depleted Scnn1b-Tg mice exhibited increased airway inflammation, the presence of neutrophilic infiltration, and increased levels of inflammatory cytokines in bronchoalveolar lavage fluid compared with Scnn1b-Tg mice. Collectively, these data identify key MΦ-mucus clearance interactions with respect to both infectious and inflammatory components of muco-obstructive lung disease.

Keywords: airway inflammation; airway mucus obstruction; alveolar macrophages; macrophage depletion; sodium channel β subunit transgenic mice.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Cytokines / immunology
  • Cytokines / metabolism
  • Diphtheria Toxin / genetics
  • Diphtheria Toxin / metabolism
  • Disease Models, Animal
  • Epithelial Sodium Channels / genetics
  • Epithelial Sodium Channels / metabolism
  • Genetic Predisposition to Disease
  • Inflammation Mediators / immunology
  • Inflammation Mediators / metabolism
  • Luminescent Proteins / genetics
  • Luminescent Proteins / metabolism
  • Lung / immunology*
  • Lung / metabolism
  • Lung / microbiology
  • Macrophages / immunology*
  • Macrophages / metabolism
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mucociliary Clearance*
  • Muramidase / genetics
  • Pasteurella Infections / genetics
  • Pasteurella Infections / immunology*
  • Pasteurella Infections / metabolism
  • Pasteurella Infections / microbiology
  • Pasteurella pneumotropica / immunology*
  • Pasteurella pneumotropica / pathogenicity
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism
  • Phenotype
  • Pneumonia, Bacterial / genetics
  • Pneumonia, Bacterial / immunology*
  • Pneumonia, Bacterial / metabolism
  • Pneumonia, Bacterial / microbiology
  • Promoter Regions, Genetic

Substances

  • Cytokines
  • Diphtheria Toxin
  • Epithelial Sodium Channels
  • Inflammation Mediators
  • Luminescent Proteins
  • Peptide Fragments
  • diphtheria toxin fragment A
  • Muramidase