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.
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.
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.
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.
► Inflammatory Ly-6Chi monocytes infiltrate arterial allografts during TA development. ► Hyperlipidemia potently accelerates Ly-6Chi monocyte recruitment into the neointima. ► TA severity correlates well with plasma cholesterol and macrophage accumulation. ► Macrophage-derived foam cell accumulation occurs independently of T lymphocytes. ► Ly-6Chi monocyte and neutrophil depletion inhibits TA development.