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

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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

Srinu Tumpara

Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany

Competing interests
No competing interests declared.
Matthias Ballmaier

Cell Sorting Core Facility, Hannover Medical School, Hannover, Germany

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0002-1352-5995
Sabine Wrenger

Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0002-9733-6162
Mandy König

Research & Development (R&D), 8sens.biognostic GmbH, Hannover, Germany

Competing interests
No competing interests declared.
Matthias Lehmann

Research & Development (R&D), 8sens.biognostic GmbH, Hannover, Germany

Competing interests
No competing interests declared.
Ralf Lichtinghagen

Institute of Clinical Chemistry, Hannover Medical School, Hannover, Germany

Competing interests
No competing interests declared.
Beatriz Martinez-Delgado

Institute of Rare Diseases Research, Instituto de Salud Carlos III, MAJADAHONDA, Spain

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0001-6834-350X
Elena Korenbaum

Institute for Biophysical Chemistry, Hannover Medical School, Hannover, Germany

Competing interests
No competing interests declared.
David DeLuca

Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0002-0141-9116
Nils Jedicke

Department of Gastroenterology, Hannover Medical School, Hannover, Germany

Competing interests
No competing interests declared.
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.
Malin Fromme

Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Medical Clinic III, Aachen, Germany

Competing interests
No competing interests declared.
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.
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.
Sabina Janciauskiene

Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany

For correspondence
janciauskiene.sabina@mh-hannover.de

Competing interests
No competing interests declared.

"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).

Copyright

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.