Alpha-1 antitrypsin deficiency impairs lung antibacterial immunity in mice

• Main Authors: Lena Ostermann, Regina Maus, Jennifer Stolper, Lisanne Schütte, Konstantina Katsarou, Srinu Tumpara, Andreas Pich, Christian Mueller, Sabina Janciauskiene, Tobias Welte, Ulrich A. Maus
• Format: Article
• Language: English
• Published: American Society for Clinical investigation 2021-02-01
• Series: JCI Insight
• Subjects: Pulmonology
• Online Access: https://doi.org/10.1172/jci.insight.140816

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.