Alpha-1 antitrypsin-deficient macrophages have increased matriptase-mediated proteolytic activity

Karina Krotova, George W. Marek, Rejean L. Wang, George Aslanidi, Brad E. Hoffman, Nazli Khodayari, Farshid N. Rouhani, Mark L. Brantly

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

Alpha-1 antitrypsin (AAT) deficiency-associated emphysema is largely attributed to insufficient inhibition of neutrophil elastase released from neutrophils. Correcting AAT levels using augmentation therapy only slows disease progression, and that suggests a more complex process of lung destruction. Because alveolar macrophages (MΦ) express AAT, we propose that the expression and intracellular accumulation of mutated Z-AAT (the most common mutation) compromisesMΦ function and contributes to emphysema development. Extracellular matrix (ECM) degradation is a hallmark of emphysema pathology. In this study,MΦ from individuals with Z-AAT (Z-MΦ) have greater proteolytic activity onECMthan do normalMΦ. This abnormal Z-MΦ activity is not abrogated by supplementation with exogenous AAT and is likely the result of cellular dysfunction induced by intracellular accumulation of Z-AAT. Using pharmacologic inhibitors, we show that several classes of proteases are involved in matrix degradation by Z-MΦ. Importantly, compared with normal MΦ, the membranebound serine protease, matriptase, is present in Z-MΦ at higher levels and contributes to their proteolytic activity on ECM. In addition, we identified matrix metalloproteinase (MMP)-14, a membraneanchored metalloproteinase, as a novel substrate for matriptase, and showed that matriptase regulates the levels of MMP-14 on the cell surface. Thus, high levels of matriptase may contribute to increased ECM degradation by Z-MΦ, both directly and through MMP-14 activation. In summary, the expression of Z-AAT in MΦ confers increased proteolytic activity on ECM. This proteolytic activity is not rescued by exogenous AAT supplementation and could thus contribute to augmentation resistance in AAT deficiency-associated emphysema.

Original languageEnglish (US)
Pages (from-to)238-247
Number of pages10
JournalAmerican journal of respiratory cell and molecular biology
Volume57
Issue number2
DOIs
StatePublished - Aug 2017

Keywords

  • Alpha-1 antitrypsin deficiency
  • Extracellular matrix degradation
  • Macrophages
  • Matriptase
  • Matrix metalloproteinase-14

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