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Molecular Medicine

, Volume 17, Issue 9–10, pp 865–874 | Cite as

Acute-Phase Protein α1-Antitrypsin Inhibits Neutrophil Calpain I and Induces Random Migration

  • Mariam Al-Omari
  • Elena Korenbaum
  • Matthias Ballmaier
  • Ulrich Lehmann
  • Danny Jonigk
  • Dietmar J. Manstein
  • Tobias Welte
  • Ravi Mahadeva
  • Sabina Janciauskiene
Invited Research Article

Abstract

A rapid recruitment of neutrophils to sites of injury or infection is a hallmark of the inflammatory response and is required for effective host defense against pathogenic stimuli. However, neutrophil-mediated inflammation can also lead to chronic tissue destruction; therefore, a better understanding of the mechanisms underlying neutrophil influx and activation is of critical importance. We have previously shown that the acute phase protein α1-antitrypsin (AAT) inhibits neutrophil chemotaxis. In this study, we examine mechanisms related to the effect of AAT on neutrophil responses. We report a previously unknown function of AAT to inactivate calpain I (μ-calpain) and to induce a rapid cell polarization and random migration. These effects of AAT coincided with a transient rise in intracellular calcium, increase in intracellular lipids, activation of the Rho GTPases, Rac1 and Cdc42, and extracellular signal-regulated kinase (ERK1/2). Furthermore, AAT caused a significant inhibition of nonstimulated as well as formyl-metleu-phe (fMLP)-stimulated neutrophil adhesion to fibronectin, strongly inhibited lipopolysaccharide-induced IL-8 release and slightly delayed neutrophil apoptosis. The results presented here broaden our understanding of the regulation of calpain-related neutrophil functional activities, and provide the impetus for new studies to define the role of AAT and other acute phase proteins in health and disease.

Notes

Acknowledgments

This study was supported by the Swedish Research Council (SJ) and Hannover Medical School. RM was supported by the Cambridge National Institute for Health Research (NIHR) Biomedical Research Centre.

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Copyright information

© The Feinstein Institute for Medical Research 2011
www.feinsteininstitute.org

Authors and Affiliations

  • Mariam Al-Omari
    • 1
    • 5
  • Elena Korenbaum
    • 2
    • 5
  • Matthias Ballmaier
    • 3
    • 5
  • Ulrich Lehmann
    • 4
    • 5
  • Danny Jonigk
    • 4
    • 5
  • Dietmar J. Manstein
    • 2
    • 5
  • Tobias Welte
    • 1
    • 5
  • Ravi Mahadeva
    • 4
    • 5
  • Sabina Janciauskiene
    • 1
    • 5
  1. 1.Department of PulmonologyHannover Medical SchoolHannoverGermany
  2. 2.Department of Biophysical ChemistryHannover Medical SchoolHannoverGermany
  3. 3.Cell Sorting Core FacilityHannover Medical SchoolHannoverGermany
  4. 4.Department of PathologyHannover Medical SchoolHannoverGermany
  5. 5.Department of Respiratory MedicineUniversity of CambridgeCambridgeUK

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