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Thromb Haemost 2016; 115(05): 1010-1024
DOI: 10.1160/TH15-08-0640
Blood Cells, Inflammation and Infection
Schattauer GmbH

PreImplantation factor prevents atherosclerosis via its immunomodulatory effects without affecting serum lipids

Yung Chih Chen   *
1   Baker IDI Heart & Diabetes Institute, Melbourne, Victoria, Australia
,
Jennifer Rivera   *
1   Baker IDI Heart & Diabetes Institute, Melbourne, Victoria, Australia
,
Melissa Fitzgerald
1   Baker IDI Heart & Diabetes Institute, Melbourne, Victoria, Australia
2   Departments of Medicine and Immunology, Monash University, Melbourne, Victoria, Australia
,
Christian Hausding
1   Baker IDI Heart & Diabetes Institute, Melbourne, Victoria, Australia
,
Ya-Lan Ying
1   Baker IDI Heart & Diabetes Institute, Melbourne, Victoria, Australia
2   Departments of Medicine and Immunology, Monash University, Melbourne, Victoria, Australia
,
Xiaowei Wang
1   Baker IDI Heart & Diabetes Institute, Melbourne, Victoria, Australia
2   Departments of Medicine and Immunology, Monash University, Melbourne, Victoria, Australia
,
Krassimira Todorova
3   Academician Bratanov Institute of Biology and Immunology of Reproduction, Bulgarian Academy of Sciences, Sofia, Bulgaria
,
Soren Hayrabedyan
3   Academician Bratanov Institute of Biology and Immunology of Reproduction, Bulgarian Academy of Sciences, Sofia, Bulgaria
,
Eytan R. Barnea   #
4   Society for the Investigation of Early Pregnancy (SIEP) and BioIncept, LLC, Cherry Hill, New Jersey, USA
,
Karlheinz Peter   #
1   Baker IDI Heart & Diabetes Institute, Melbourne, Victoria, Australia
2   Departments of Medicine and Immunology, Monash University, Melbourne, Victoria, Australia
› Author Affiliations
Further Information

Publication History

Received: 12 August 2015

Accepted after major revision: 11 January 2016

Publication Date:
06 December 2017 (online)

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Summary

PreImplantation factor (PIF) is a 15-amino acid peptide endogenously secreted by viable embryos, regulating/enabling maternal (host) acceptance/tolerance to the “invading” embryo (allograft) all-while preserving maternal immunity to fight infections. Such attributes make PIF a potential therapeutic agent for chronic inflammatory diseases. We investigated whether PIF’s immunomodulatory properties prevent progression of atherosclerosis in the hyper-cholesterolaemic ApoEdeficient murine model. Male, high-fat diet fed, ApoE-deficient (ApoE-/-) mice were administered either PBS, scrambled PIF (0.3–3 mg/kg) or PIF (0.3–3 mg/kg) for seven weeks. After treatment, PIF (3 mg/kg)-treated ApoE-/- mice displayed significantly reduced atherosclerosis lesion burden in the aortic sinus and aortic arch, without any effect on lipid profile. PIF also caused a significant reduction in infiltration of macrophages, decreased expression of pro-inflammatory adhesion molecules, cytokines and chemokines in the plaque, and reduced circulating IFN-γ levels. PIF preferentially binds to monocytes/neutrophils. In vitro, PIF attenuated monocyte migration (MCP-1-induced chemotaxis assay) and in vivo in LPS peritonitis model. Also PIF prevented leukocyte extravasation (peritonitis thioglycollate-induced model), demonstrating that PIF exerts its effect in part by modulation of monocyte function. Inhibition of the potassium channel KCNAB3 (Kv1.3) and of the insulin degrading enzyme (IDE) was demonstrated as potential mechanism of PIF’s immunomodulatory effects. In conclusion, PIF regulates/lowers inflammation and prevents atherosclerosis development without affecting circulating lipids. Overall our findings establish PIF as a strong immunomodulatory drug candidate for atherosclerosis therapy.

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

Keywords

Atherosclerosis - immune cells - ApoE-deficient mice - PreImplantation Factor (PIF) - macrophage - immunomodulatory therapy

* YCC and JF contributed equally


# ERB and KP contributed equally.


 

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