Alpha-1 antitrypsin deficiency impairs lung antibacterial immunity in mice

JCI Insight. 2021 Feb 8;6(3):e140816. doi: 10.1172/jci.insight.140816.

Abstract

Alpha-1 antitrypsin (AAT) is a major inhibitor of serine proteases in mammals. Therefore, its deficiency leads to protease-antiprotease imbalance and a risk for developing lung emphysema. Although therapy with human plasma-purified AAT attenuates AAT deficiency-related emphysema, its impact on lung antibacterial immunity is poorly defined. Here, we examined the effect of AAT therapy on lung protective immunity in AAT-deficient (KO) mice challenged with Streptococcus pneumoniae. AAT-KO mice were highly susceptible to S. pneumoniae, as determined by severe lobar pneumonia and early mortality. Mechanistically, we found that neutrophil-derived elastase (NE) degraded the opsonophagocytically important collectins, surfactant protein A (SP-A) and D (SP-D), which was accompanied by significantly impaired lung bacterial clearance in S. pneumoniae-infected AAT-KO mice. Treatment of S. pneumoniae-infected AAT-KO mice with human AAT protected SP-A and SP-D from NE-mediated degradation and corrected the pulmonary pathology observed in these mice. Likewise, treatment with Sivelestat, a specific inhibitor of NE, also protected collectins from degradation and significantly decreased bacterial loads in S. pneumoniae-infected AAT-KO mice. Our findings show that NE is responsible for the degradation of lung SP-A and SP-D in AAT-KO mice affecting lung protective immunity in AAT deficiency.

Keywords: Bacterial infections; Neutrophils; Proteases; Pulmonology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Female
  • Humans
  • Lung / immunology*
  • Lung / metabolism
  • Lung / microbiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Pneumonia, Pneumococcal / drug therapy
  • Pneumonia, Pneumococcal / etiology
  • Pneumonia, Pneumococcal / immunology
  • Pulmonary Emphysema / etiology
  • Streptococcus pneumoniae / immunology*
  • Streptococcus pneumoniae / pathogenicity*
  • alpha 1-Antitrypsin / genetics
  • alpha 1-Antitrypsin / immunology
  • alpha 1-Antitrypsin / metabolism
  • alpha 1-Antitrypsin / pharmacokinetics
  • alpha 1-Antitrypsin / therapeutic use
  • alpha 1-Antitrypsin Deficiency / complications
  • alpha 1-Antitrypsin Deficiency / genetics
  • alpha 1-Antitrypsin Deficiency / immunology*

Substances

  • SERPINA1 protein, human
  • Serpina1a protein, mouse
  • alpha 1-Antitrypsin