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CXCR4 blockade induces atherosclerosis by affecting neutrophil function.

ABSTRACT: The SDF-1?/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.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? antagonist or CXCR4 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.In conclusion, CXCR4 contributes to later stages of plaque progression by perturbing neutrophil function.

SUBMITTER: Bot I

PROVIDER: S-EPMC4418455 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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CXCR4 blockade induces atherosclerosis by affecting neutrophil function.

Bot Ilze I Daissormont Isabelle T M N IT Zernecke Alma A van Puijvelde Gijs H M GH Kramp Birgit B de Jager Saskia C A SC Sluimer Judith C JC Manca Marco M Hérias Veronica V Westra Marijke M MM Bot Martine M van Santbrink Peter J PJ van Berkel Theo J C TJ Su Lishan L Skjelland Mona M Gullestad Lars L Kuiper Johan J Halvorsen Bente B Aukrust Paul P Koenen Rory R RR Weber Christian C Biessen Erik A L EA

Journal of molecular and cellular cardiology 20140508

<h4>Aims</h4>The SDF-1α/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.<h4>Methods and results</h4>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 advan ...[more]

PMID: 24816217

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Project description:ObjectivesTrauma predisposes to systemic sterile inflammation (systemic inflammatory response syndrome) as well as infection, but the mechanisms linking injury to infection are poorly understood. Mitochondrial debris contains formyl peptides. These bind formyl peptide receptor-1, trafficking neutrophils to wounds, initiating systemic inflammatory response syndrome, and wound healing. Bacterial formyl peptides, however, also attract neutrophils via formyl peptide receptor-1. Thus, mitochondrial formyl peptides might suppress neutrophils antimicrobial function. Also, formyl peptide receptor-1 blockade used to mitigate systemic inflammatory response syndrome might predispose to sepsis. We examined how mitochondrial formyl peptides impact neutrophils functions contributing to antimicrobial responses and how formyl peptide receptor-1 antagonists affect those functions.DesignProspective study of human and murine neutrophils and clinical cohort analysis.SettingUniversity research laboratory and level 1 trauma center.PatientsTrauma patients, volunteer controls.Animal subjectsC57Bl/6, formyl peptide receptor-1, and formyl peptide receptor-2 knockout mice.InterventionsHuman and murine neutrophils functions were activated with autologous mitochondrial debris, mitochondrial formyl peptides, or bacterial formyl peptides followed by chemokines or leukotrienes. The experiments were repeated using formyl peptide receptor-1 antagonist cyclosporin H, "designer" human formyl peptide receptor-1 antagonists (POL7178 and POL7200), or anti-formyl peptide receptor-1 antibodies. Mouse injury/lung infection model was used to evaluate effect of formyl peptide receptor-1 inhibition.Measurements and main resultsHuman neutrophils cytosolic calcium, chemotaxis, reactive oxygen species production, and phagocytosis were studied before and after exposure to mitochondrial debris, mitochondrial formyl peptides, and bacterial formyl peptides. Mitochondrial formyl peptide and bacterial formyl peptides had similar effects on neutrophils. Responses to chemokines and leukotrienes were suppressed by prior exposure to formyl peptides. POL7200 and POL7178 were specific antagonists of human formyl peptide receptor-1 and more effective than cyclosporin H or anti-formyl peptide receptor-1 antibodies. Formyl peptides inhibited mouse neutrophils responses to chemokines only if formyl peptide receptor-1 was present. Formyl peptide receptor-1 blockade did not inhibit neutrophils bacterial phagocytosis or reactive oxygen species production. Cyclosporin H increased bacterial clearance in lungs after injury.ConclusionsFormyl peptides both activate and desensitize neutrophils. Formyl peptide receptor-1 blockade prevents desensitization, potentially both diminishing systemic inflammatory response syndrome and protecting the host against secondary infection after tissue trauma or primary infection.

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CXCR4 blockade induces atherosclerosis by affecting neutrophil function.

Publications

CXCR4 blockade induces atherosclerosis by affecting neutrophil function.

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