Inflammatory Ly-6C(hi) monocytes play an important role in the development of severe transplant arteriosclerosis in hyperlipidemic recipients

Research output: Contribution to journalArticle

Abstract

Objective: Transplant arteriosclerosis (TA) restricts long-term survival of heart transplant recipients. Although the role of monocyte/macrophages is well established in native atherosclerosis, it has been studied to a much lesser extent in TA. Plasma cholesterol is the most important non-immunologic risk factor for development of TA but the underlying mechanisms are largely unknown. We hypothesized that monocyte/macrophages might play an important role in the pathogenesis of TA under hyperlipidemic conditions. Methods: We studied TA in fully mismatched arterial allografts transplanted into hyperlipidemic ApoE(-/-) recipients compared to wild-type controls. The recruitment of distinct monocyte populations into the grafts was tracked by in vivo labelling with fluorescent microspheres. We used antibody-mediated depletion protocols to dissect the relative contribution of T lymphocytes and monocytes to disease development. Results: In the hyperlipidemic environment the progression of TA was highly exacerbated and the inflammatory CD11b(+)CD115(+)Ly-6C(hi) monocytes were preferentially recruited into the neointima. The number of macrophage-derived foam cells present in the grafts strongly correlated with plasma cholesterol and disease severity. Depletion of Ly-6C(hi) monocytes and neutrophils significantly inhibited macrophage accumulation and disease progression. The accelerated monocyte recruitment occurs through a T cell-independent mechanism, as T cell depletion did not influence macrophage accumulation into the grafts. Conclusions: Our study identifies for the first time the involvement of inflammatory Ly-6C(hi) monocytes into the pathogenesis of TA, particularly in conditions of hyperlipidemia. Targeted therapies modulating the recruitment and activation of these cells could potentially delay coronary allograft vasculopathy and improve long-term survival of heart transplant recipients. (C) 2012 Elsevier Ireland Ltd. All rights reserved.

Details

Authors
  • Alexandru Schiopu
  • Satish N. Nadig
  • Ovidiu S. Cotoi
  • Joanna Hester
  • Nico van Rooijen
  • Kathryn J. Wood
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cardiac and Cardiovascular Systems

Keywords

  • Transplant vasculopathy, Hypercholesterolemia, Inflammation, Monocytes, Macrophages
Original languageEnglish
Pages (from-to)291-298
JournalAtherosclerosis
Volume223
Issue number2
StatePublished - 2012
Peer-reviewedYes