Anti-inflammatory and immunomodulatory properties of α1-antitrypsin without inhibition of elastase

Danny Jonigk, Mariam Al-Omari, Lavinia Maegel, Meike Müller, Nicole Izykowski, Jaewoo Hong, Kwangwon Hong, Soo Hyun Kim, Martina Dorsch, Ravi Mahadeva, Florian Laenger, Hans Kreipe, Armin Braun, Galit Shahaf, Eli C. Lewis, Tobias Welte, Charles A. Dinarello, Sabina Janciauskiene

Research output: Contribution to journalArticlepeer-review

197 Scopus citations

Abstract

The rationale of α1-antitrypsin (AAT) augmentation therapy to treat progressive emphysema in AAT-deficient patients is based on inhibition of neutrophil elastase; however, the benefit of this treatment remains unclear. Here we show that clinical grade AAT (with elastase inhibitory activity) and a recombinant form of AAT (rAAT) without anti-elastase activity reduces lung inflammatory responses to LPS in elastase-deficient mice. WT and elastase-deficient mice treated with either native AAT or rAAT exhibited significant reductions in infiltrating neutrophils (23% and 68%), lavage fluid levels of TNF-α (70% and 80%), and the neutrophil chemokine KC (CXCL1) (64% and 90%), respectively. Lung parenchyma TNF-α, DNA damage-inducible transcript 3 and X-box binding protein-1 mRNA levels were reduced in both mouse strains treated with AAT; significantly lower levels of these genes, as well as IL-1β gene expression, were observed in lungs of AAT-deficient patients treated with AAT therapy compared with untreated patients. In vitro, LPS-induced cytokines from WT and elastase-deficient mouse neutrophils, as well as neutrophils of healthy humans, were similarly reduced by AAT or rAAT; human neutrophils adhering to endothelial cells were decreased by 60-80% (P < 0.001) with either AAT or rAAT. In mouse pancreatic islet macrophages, LPS-induced surface expression of MHC II, Toll-like receptor-2 and -4 were markedly lower (80%, P < 0.001) when exposed to either AAT or rAAT. Consistently, in vivo and in vitro, rAAT reduced inflammatory responses at concentrations 40- to 100-fold lower than native plasma-derived AAT. These data provide evidence that the anti-inflammatory and immunomodulatory properties of AAT can be independent of elastase inhibition.

Original languageEnglish
Pages (from-to)15007-15012
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number37
DOIs
StatePublished - 10 Sep 2013

Keywords

  • Alpha 1-antitrypsin
  • Immunomodulation
  • Inflammation

ASJC Scopus subject areas

  • General

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