CD70 limits atherosclerosis and promotes macrophage function

Holger Winkels; Svenja Meiler; Esther Smeets; Dirk Lievens; David Engel; Charlotte Spitz; Christina Bürger; Petteri Rinne; Linda Beckers; Angelika Dandl; Sigrid Reim; Maiwand Ahmadsei; Jan Van den Bossche; Lesca M. Holdt; Remco T. A. Megens; Martin M. Schmitt; Menno de Winther; Eric A. Biessen; Jannie Borst; Alexander Faussner; Christian Weber; Esther Lutgens; Norbert Gerdes

doi:10.1160/TH16-04-0318

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2017; 117(01): 164-175
DOI: 10.1160/TH16-04-0318

Atherosclerosis and Ischaemic Disease

Schattauer GmbH

CD70 limits atherosclerosis and promotes macrophage function

Holger Winkels^*,#

¹Institute for Cardiovascular Prevention (IPEK), LMU Munich, Munich, Germany

²Department of Medical Biochemistry, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands

,

Svenja Meiler^*,#

¹Institute for Cardiovascular Prevention (IPEK), LMU Munich, Munich, Germany

²Department of Medical Biochemistry, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands

,

Esther Smeets^*,#

²Department of Medical Biochemistry, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands

,

Dirk Lievens

¹Institute for Cardiovascular Prevention (IPEK), LMU Munich, Munich, Germany

,

David Engel

³Cardiovascular Research Institute Maastricht (CARIM), University of Maastricht, The Netherlands

,

Charlotte Spitz

¹Institute for Cardiovascular Prevention (IPEK), LMU Munich, Munich, Germany

,

Christina Bürger

¹Institute for Cardiovascular Prevention (IPEK), LMU Munich, Munich, Germany

,

Petteri Rinne

¹Institute for Cardiovascular Prevention (IPEK), LMU Munich, Munich, Germany

,

Linda Beckers

²Department of Medical Biochemistry, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands

,

Angelika Dandl

¹Institute for Cardiovascular Prevention (IPEK), LMU Munich, Munich, Germany

,

Sigrid Reim

¹Institute for Cardiovascular Prevention (IPEK), LMU Munich, Munich, Germany

,

Maiwand Ahmadsei

¹Institute for Cardiovascular Prevention (IPEK), LMU Munich, Munich, Germany

,

Jan Van den Bossche

²Department of Medical Biochemistry, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands

,

Lesca M. Holdt

⁷Department of Laboratory Medicine, LMU Munich, Munich, Germany

,

Remco T. A. Megens

¹Institute for Cardiovascular Prevention (IPEK), LMU Munich, Munich, Germany

³Cardiovascular Research Institute Maastricht (CARIM), University of Maastricht, The Netherlands

,

Martin M. Schmitt

¹Institute for Cardiovascular Prevention (IPEK), LMU Munich, Munich, Germany

,

Menno de Winther

¹Institute for Cardiovascular Prevention (IPEK), LMU Munich, Munich, Germany

²Department of Medical Biochemistry, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands

,

Eric A. Biessen

³Cardiovascular Research Institute Maastricht (CARIM), University of Maastricht, The Netherlands

⁵Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen, Aachen, Germany

,

Jannie Borst

⁴Division of Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

,

Alexander Faussner

¹Institute for Cardiovascular Prevention (IPEK), LMU Munich, Munich, Germany

,

Christian Weber

¹Institute for Cardiovascular Prevention (IPEK), LMU Munich, Munich, Germany

³Cardiovascular Research Institute Maastricht (CARIM), University of Maastricht, The Netherlands

⁶DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany

,

Esther Lutgens^*,#

¹Institute for Cardiovascular Prevention (IPEK), LMU Munich, Munich, Germany

²Department of Medical Biochemistry, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands

,

Norbert Gerdes^*,#

¹Institute for Cardiovascular Prevention (IPEK), LMU Munich, Munich, Germany

²Department of Medical Biochemistry, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands

› Author Affiliations

Abstract

Summary

The costimulatory molecule CD70 is expressed on activated immune cells and is known to modulate responses of T, B, and NK cells via its receptor CD27. Until now, there is only limited data describing the role of CD70 in atherosclerosis. We observed that ruptured human carotid atherosclerotic plaques displayed higher CD70 expression than stable carotid atherosclerotic plaques, and that CD70 expression in murine atheroma localized to macrophages. Lack of CD70 impaired the inflammatory capacity (e. g. reactive oxygen species and nitric oxide production) of bone marrow-derived macrophages, increased both M1-like and M2-like macrophage markers, and rendered macrophages meta-bolically inactive and prone to apoptosis. Moreover, CD70-deficient macrophages expressed diminished levels of scavenger receptors and ABC-transporters, impairing uptake of oxidised low-density lipoprotein (oxLDL) and cholesterol efflux, respectively. Hyperlipidaemic Apoe ^−/− mice reconstituted with CD70-deficient bone marrow displayed a profound increase in necrotic core size, plaque area, and number of lesional macrophages as compared to mice receiving control bone marrow. Accordingly, 18 week-old, chow diet-fed CD70-deficient Apoe^−/−mice displayed larger atheroma characterised by lower cellularity and more advanced plaque phenotype than Apoe^−/− mice. In conclusion, CD70 promotes macrophage function and viability and is crucial for effective phagocytosis and efflux of oxLDL. Deficiency in CD70 results in more advanced atheroma. Our data suggest that CD70 mitigates atherosclerosis at least in part by modulating macrophage function.

Note: The review process for this manuscript was fully handled by G. Y. H. Lip, Editor in Chief.

Supplementary Material to this article is available online at www.thrombosis-online.com.

Keywords

Atherosclerosis - inflammation - macrophages - CD70

Full Text

References

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Supplementary Material

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