Polymerization of misfolded Z alpha-1antitrypin protein lowers CX3CR1 expression in human PBMCs

  1. Srinu Tumpara
  2. Matthias Ballmaier
  3. Sabine Wrenger
  4. Mandy König
  5. Matthias Lehmann
  6. Ralf Lichtinghagen
  7. Beatriz Martinez-Delgado
  8. Elena Korenbaum
  9. David DeLuca
  10. Nils Jedicke
  11. Tobias Welte
  12. Malin Fromme
  13. Pavel Strnad
  14. Jan Stolk
  15. Sabina Janciauskiene  Is a corresponding author
  1. Hannover Medical School, Germany
  2. 8sens.biognostic GmbH, Germany
  3. Instituto de Salud Carlos III, Spain
  4. University Hospital RWTH Aachen, Medical Clinic III, Germany
  5. University 18 Hospital RWTH Aachen, Germany
  6. Leiden University Medical Center, Netherlands

Abstract

The CX3CR1 (chemokine (C-X3-C motif) receptor 1) expression levels on immune cells have significant importance in maintaining tissue homeostasis under physiological and pathological conditions. The factors implicated in the regulation of CX3CR1 and its specific ligand CX3CL1 (fractalkine) expression remain largely unknown. Recent studies provide evidence that host`s misfolded proteins occurring in the forms of polymers or amyloid fibrils can regulate CX3CR1 expression. Herein, a novel example demonstrates that polymers of human ZZ alpha-1 antitrypsin (Z-AAT) protein, resulting from its conformational misfolding due to the Z (Glu342Lys) mutation in SERPINA1 gene, strongly lower CX3CR1 mRNA expression in human PBMCs. This parallels with increase of intracellular levels of CX3CR1 and Z-AAT proteins. Presented data indicate the involvement of the CX3CR1 pathway in the Z-AAT-related disorders and further support the role of misfolded proteins in CX3CR1 regulation.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures

Article and author information

Author details

  1. Srinu Tumpara

    Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany
    Competing interests
    No competing interests declared.
  2. Matthias Ballmaier

    Cell Sorting Core Facility, Hannover Medical School, Hannover, Germany
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1352-5995
  3. Sabine Wrenger

    Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9733-6162
  4. Mandy König

    Research & Development (R&D), 8sens.biognostic GmbH, Hannover, Germany
    Competing interests
    No competing interests declared.
  5. Matthias Lehmann

    Research & Development (R&D), 8sens.biognostic GmbH, Hannover, Germany
    Competing interests
    No competing interests declared.
  6. Ralf Lichtinghagen

    Institute of Clinical Chemistry, Hannover Medical School, Hannover, Germany
    Competing interests
    No competing interests declared.
  7. Beatriz Martinez-Delgado

    Institute of Rare Diseases Research, Instituto de Salud Carlos III, MAJADAHONDA, Spain
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6834-350X
  8. Elena Korenbaum

    Institute for Biophysical Chemistry, Hannover Medical School, Hannover, Germany
    Competing interests
    No competing interests declared.
  9. David DeLuca

    Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0141-9116
  10. Nils Jedicke

    Department of Gastroenterology, Hannover Medical School, Hannover, Germany
    Competing interests
    No competing interests declared.
  11. Tobias Welte

    Department of Gastroenterology, Hannover Medical School, Hannover, Germany
    Competing interests
    Tobias Welte, reports grants from German Ministry of Research and Education, during the conduct of the study; personal fees from Grifols, CSL Behring, outside the submitted work.
  12. Malin Fromme

    Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Medical Clinic III, Aachen, Germany
    Competing interests
    No competing interests declared.
  13. Pavel Strnad

    University 18 Hospital RWTH Aachen, Aachen, Germany
    Competing interests
    Pavel Strnad, reports grants and personal fees from CSL Behring, grants and personal fees from Grifols Inc, personal fees from Dicerna Inc, grants from Vertex, grants from Arrowhead, outside the submitted work.
  14. Jan Stolk

    Department of Pulmonology, Leiden University Medical Center, Leiden, Netherlands
    Competing interests
    Jan Stolk, reports grants from CSL Behring, grants from Kamada LtD, during the conduct of the study.
  15. Sabina Janciauskiene

    Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany
    For correspondence
    janciauskiene.sabina@mh-hannover.de
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3228-8021

Funding

Deutsche Forschungsgemeinschaft (STR 1095/6-1)

  • Pavel Strnad

Deutsche Zentrum für Lungenforschung (82DZL002A)

  • Sabina Janciauskiene

Deutsche Forschungsgemeinschaft (SFB/TRR57)

  • Pavel Strnad

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: The institutional review board of Aachen University (EK 173/15) provided ethical approval for individuals recruited in Germany. Leiden University Medical Center provided ethical approval (project P00.083 and P01.101) for the second study group. For all individuals detailed medical records data were anonymized. All participants issued a written informed consent according to the ethical guidelines of the Helsinki Declaration (Hong Kong Amendment) as well as Good Clinical Practice (European guidelines).

Reviewing Editor

  1. Koyeli Mapa, Shiv Nadar University, India

Publication history

  1. Received: November 13, 2020
  2. Accepted: May 16, 2021
  3. Accepted Manuscript published: May 18, 2021 (version 1)
  4. Version of Record published: June 15, 2021 (version 2)

Copyright

© 2021, Tumpara et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Srinu Tumpara
  2. Matthias Ballmaier
  3. Sabine Wrenger
  4. Mandy König
  5. Matthias Lehmann
  6. Ralf Lichtinghagen
  7. Beatriz Martinez-Delgado
  8. Elena Korenbaum
  9. David DeLuca
  10. Nils Jedicke
  11. Tobias Welte
  12. Malin Fromme
  13. Pavel Strnad
  14. Jan Stolk
  15. Sabina Janciauskiene
(2021)
Polymerization of misfolded Z alpha-1antitrypin protein lowers CX3CR1 expression in human PBMCs
eLife 10:e64881.
https://doi.org/10.7554/eLife.64881

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