CXCR4 blockade induces atherosclerosis by affecting neutrophil function

Ilze Bot; Isabelle T. M. N. Daissormont; Alma Zernecke; Gijs H. M. van Puijvelde; Birgit Kramp; Saskia C. A. de Jager; Judith C. Sluimer; Marco Manca; Veronica Herias; Marijke M. Westra; Martine Bot; Peter J. van Santbrink; Theo J. C. van Berkel; Lishan Su; Mona Skjelland; Lars Gullestad; Johan Kuiper; Bente Halvorsen; Paul Aukrust; Rory R. Koenen; Christian Weber; Erik A. L. Biessen

doi:10.1016/j.yjmcc.2014.04.021

CXCR4 blockade induces atherosclerosis by affecting neutrophil function

Ilze Bot^*, Isabelle T. M. N. Daissormont, Alma Zernecke, Gijs H. M. van Puijvelde, Birgit Kramp, Saskia C. A. de Jager, Judith C. Sluimer, Marco Manca, Veronica Herias, Marijke M. Westra, Martine Bot, Peter J. van Santbrink, Theo J. C. van Berkel, Lishan Su, Mona Skjelland, Lars Gullestad, Johan Kuiper, Bente Halvorsen, Paul Aukrust, Rory R. KoenenChristian Weber, Erik A. L. Biessen

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

Aims: The SDF-1 alpha/CXCR4 dyad was previously shown by us and others to be instrumental in intimal hyperplasia as well as early stage atherosclerosis. We here sought to investigate its impact on clinically relevant stages of atherosclerosis in mouse and man. Methods and results: Immunohistochemical analysis of CXCR4 expression in human atherosclerotic lesions revealed a progressive accumulation of CXCR4(+) cells during plaque progression. To address causal involvement of CXCR4 in advanced stages of atherosclerosis we reconstituted LDLr-/- mice with autologous bone marrow infected with lentivirus encoding SDF-1 alpha antagonist or OCCR4 degrakine, which effects proteasomal degradation of CXCR4. Functional CXCR4 blockade led to progressive plaque expansion with disease progression, while also promoting intraplaque haemorrhage. Moreover, CXCR4 knockdown was seen to augment endothelial adhesion of neutrophils. Concordant with this finding, inhibition of CXCR4 function increased adhesive capacity and reduced apoptosis of neutrophils and resulted in hyperactivation of circulating neutrophils. Compatible with a role of the neutrophil CXCR4 in end-stage atherosclerosis, CXCR4 expression by circulating neutrophils was lowered in patients with acute cardiovascular syndromes. Conclusion: In conclusion, OCCR4 contributes to later stages of plaque progression by perturbing neutrophil function.

Original language	English
Pages (from-to)	44-52
Journal	Journal of Molecular and Cellular Cardiology
Volume	74
DOIs	https://doi.org/10.1016/j.yjmcc.2014.04.021
Publication status	Published - Sep 2014

Keywords

atherosclerosis
neutrophils
CXCR4
SDF-1 alpha
senescence

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10.1016/j.yjmcc.2014.04.021

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Cite this

Bot, I., Daissormont, I. T. M. N., Zernecke, A., van Puijvelde, G. H. M., Kramp, B., de Jager, S. C. A., Sluimer, J. C., Manca, M., Herias, V., Westra, M. M., Bot, M., van Santbrink, P. J., van Berkel, T. J. C., Su, L., Skjelland, M., Gullestad, L., Kuiper, J., Halvorsen, B., Aukrust, P., ... Biessen, E. A. L. (2014). CXCR4 blockade induces atherosclerosis by affecting neutrophil function. Journal of Molecular and Cellular Cardiology, 74, 44-52. https://doi.org/10.1016/j.yjmcc.2014.04.021

@article{803309f51df042b38c901571cbc042a4,

title = "CXCR4 blockade induces atherosclerosis by affecting neutrophil function",

abstract = "Aims: The SDF-1 alpha/CXCR4 dyad was previously shown by us and others to be instrumental in intimal hyperplasia as well as early stage atherosclerosis. We here sought to investigate its impact on clinically relevant stages of atherosclerosis in mouse and man. Methods and results: Immunohistochemical analysis of CXCR4 expression in human atherosclerotic lesions revealed a progressive accumulation of CXCR4(+) cells during plaque progression. To address causal involvement of CXCR4 in advanced stages of atherosclerosis we reconstituted LDLr-/- mice with autologous bone marrow infected with lentivirus encoding SDF-1 alpha antagonist or OCCR4 degrakine, which effects proteasomal degradation of CXCR4. Functional CXCR4 blockade led to progressive plaque expansion with disease progression, while also promoting intraplaque haemorrhage. Moreover, CXCR4 knockdown was seen to augment endothelial adhesion of neutrophils. Concordant with this finding, inhibition of CXCR4 function increased adhesive capacity and reduced apoptosis of neutrophils and resulted in hyperactivation of circulating neutrophils. Compatible with a role of the neutrophil CXCR4 in end-stage atherosclerosis, CXCR4 expression by circulating neutrophils was lowered in patients with acute cardiovascular syndromes. Conclusion: In conclusion, OCCR4 contributes to later stages of plaque progression by perturbing neutrophil function. ",

keywords = "atherosclerosis, neutrophils, CXCR4, SDF-1 alpha, senescence",

author = "Ilze Bot and Daissormont, {Isabelle T. M. N.} and Alma Zernecke and {van Puijvelde}, {Gijs H. M.} and Birgit Kramp and {de Jager}, {Saskia C. A.} and Sluimer, {Judith C.} and Marco Manca and Veronica Herias and Westra, {Marijke M.} and Martine Bot and {van Santbrink}, {Peter J.} and {van Berkel}, {Theo J. C.} and Lishan Su and Mona Skjelland and Lars Gullestad and Johan Kuiper and Bente Halvorsen and Paul Aukrust and Koenen, {Rory R.} and Christian Weber and Biessen, {Erik A. L.}",

year = "2014",

month = sep,

doi = "10.1016/j.yjmcc.2014.04.021",

language = "English",

volume = "74",

pages = "44--52",

journal = "Journal of Molecular and Cellular Cardiology",

issn = "0022-2828",

publisher = "ELSEVIER SCI LTD",

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Bot, I, Daissormont, ITMN, Zernecke, A, van Puijvelde, GHM, Kramp, B, de Jager, SCA, Sluimer, JC, Manca, M, Herias, V, Westra, MM, Bot, M, van Santbrink, PJ, van Berkel, TJC, Su, L, Skjelland, M, Gullestad, L, Kuiper, J, Halvorsen, B, Aukrust, P, Koenen, RR , Weber, C & Biessen, EAL 2014, 'CXCR4 blockade induces atherosclerosis by affecting neutrophil function', Journal of Molecular and Cellular Cardiology, vol. 74, pp. 44-52. https://doi.org/10.1016/j.yjmcc.2014.04.021

TY - JOUR

T1 - CXCR4 blockade induces atherosclerosis by affecting neutrophil function

AU - Bot, Ilze

AU - Daissormont, Isabelle T. M. N.

AU - Zernecke, Alma

AU - van Puijvelde, Gijs H. M.

AU - Kramp, Birgit

AU - de Jager, Saskia C. A.

AU - Sluimer, Judith C.

AU - Manca, Marco

AU - Herias, Veronica

AU - Westra, Marijke M.

AU - Bot, Martine

AU - van Santbrink, Peter J.

AU - van Berkel, Theo J. C.

AU - Su, Lishan

AU - Skjelland, Mona

AU - Gullestad, Lars

AU - Kuiper, Johan

AU - Halvorsen, Bente

AU - Aukrust, Paul

AU - Koenen, Rory R.

AU - Weber, Christian

AU - Biessen, Erik A. L.

PY - 2014/9

Y1 - 2014/9

N2 - Aims: The SDF-1 alpha/CXCR4 dyad was previously shown by us and others to be instrumental in intimal hyperplasia as well as early stage atherosclerosis. We here sought to investigate its impact on clinically relevant stages of atherosclerosis in mouse and man. Methods and results: Immunohistochemical analysis of CXCR4 expression in human atherosclerotic lesions revealed a progressive accumulation of CXCR4(+) cells during plaque progression. To address causal involvement of CXCR4 in advanced stages of atherosclerosis we reconstituted LDLr-/- mice with autologous bone marrow infected with lentivirus encoding SDF-1 alpha antagonist or OCCR4 degrakine, which effects proteasomal degradation of CXCR4. Functional CXCR4 blockade led to progressive plaque expansion with disease progression, while also promoting intraplaque haemorrhage. Moreover, CXCR4 knockdown was seen to augment endothelial adhesion of neutrophils. Concordant with this finding, inhibition of CXCR4 function increased adhesive capacity and reduced apoptosis of neutrophils and resulted in hyperactivation of circulating neutrophils. Compatible with a role of the neutrophil CXCR4 in end-stage atherosclerosis, CXCR4 expression by circulating neutrophils was lowered in patients with acute cardiovascular syndromes. Conclusion: In conclusion, OCCR4 contributes to later stages of plaque progression by perturbing neutrophil function.

AB - Aims: The SDF-1 alpha/CXCR4 dyad was previously shown by us and others to be instrumental in intimal hyperplasia as well as early stage atherosclerosis. We here sought to investigate its impact on clinically relevant stages of atherosclerosis in mouse and man. Methods and results: Immunohistochemical analysis of CXCR4 expression in human atherosclerotic lesions revealed a progressive accumulation of CXCR4(+) cells during plaque progression. To address causal involvement of CXCR4 in advanced stages of atherosclerosis we reconstituted LDLr-/- mice with autologous bone marrow infected with lentivirus encoding SDF-1 alpha antagonist or OCCR4 degrakine, which effects proteasomal degradation of CXCR4. Functional CXCR4 blockade led to progressive plaque expansion with disease progression, while also promoting intraplaque haemorrhage. Moreover, CXCR4 knockdown was seen to augment endothelial adhesion of neutrophils. Concordant with this finding, inhibition of CXCR4 function increased adhesive capacity and reduced apoptosis of neutrophils and resulted in hyperactivation of circulating neutrophils. Compatible with a role of the neutrophil CXCR4 in end-stage atherosclerosis, CXCR4 expression by circulating neutrophils was lowered in patients with acute cardiovascular syndromes. Conclusion: In conclusion, OCCR4 contributes to later stages of plaque progression by perturbing neutrophil function.

KW - atherosclerosis

KW - neutrophils

KW - CXCR4

KW - SDF-1 alpha

KW - senescence

U2 - 10.1016/j.yjmcc.2014.04.021

DO - 10.1016/j.yjmcc.2014.04.021

M3 - Article

C2 - 24816217

VL - 74

SP - 44

EP - 52

JO - Journal of Molecular and Cellular Cardiology

JF - Journal of Molecular and Cellular Cardiology

SN - 0022-2828

ER -