Inflammatory Ly-6Chi monocytes play an important role in the development of severe transplant arteriosclerosis in hyperlipidemic recipients

Alexandru Schiopu*, Satish N. Nadig, Ovidiu S. Cotoi, Joanna Hester, Nico Van Rooijen, Kathryn J. Wood

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

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-6Chi 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-6Chi 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-6Chi 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.

Original languageEnglish (US)
Pages (from-to)291-298
Number of pages8
JournalAtherosclerosis
Volume223
Issue number2
DOIs
StatePublished - Aug 2012
Externally publishedYes

Keywords

  • Hypercholesterolemia
  • Inflammation
  • Macrophages
  • Monocytes
  • Transplant vasculopathy

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Fingerprint

Dive into the research topics of 'Inflammatory Ly-6Chi monocytes play an important role in the development of severe transplant arteriosclerosis in hyperlipidemic recipients'. Together they form a unique fingerprint.

Cite this