Atherosclerosis - Monocyte Immunity

During atherogenesis, an inflammatory process, leukocytes and lipids accumulate in the aortic intima. Lipid-rich macrophages, known as foam cells in atheromata, secrete inflammatory mediators that stimulate smooth muscle cell migration and proliferation, and participate in plaque development. Thrombosis, the chief complication and cause of myocardial infarction and stroke, often involves rupture of a vulnerable plaque, defined by its thin fibrous cap and large lipid core. Monocyte recruitment to the intima is the hallmark of fatty streaks, the earliest grossly detectable lesion of human and experimental atherosclerosis. In the intima, monocytes differentiate into macrophages, ingest oxidized lipoproteins via scavenger receptors, and secrete inflammatory mediators that stimulate smooth muscle cell migration and proliferation. Elucidating the biology and dynamics of leukocyte recruitment to atherosclerotic lesions, therefore, is of clinical and biological importance

Monocyte Trafficking

PNAS, 2006, 103:10340
JCI, 2007, 117:195 (see also )

Monocytes participate importantly in the pathogenesis of atherosclerosis, but their spatial and temporal recruitment from circulation remains uncertain. We are using a two-step isolation method that yields viable and functionally intact peripheral blood monocyte populations for tracking studies after adoptive transfer in atherosclerotic mice. We report that monocyte accumulation in mouse atherogenesis is progressive and proportional to extent of disease (PNAS, 2006, 103:10340). Our data contribute to the concept that atheromata actively and dynamically recruit monocytes throughout their lifetime and, thus, have implications for therapeutic approaches that target monocyte adhesion and chemoattractant molecules.

Both human and mouse monocytes fall into at least two phenotypically distinct subsets: Ly-6Chi (Gr-1+ CCR2+ CX3CR1low) and Ly-6Clo (Gr-1- CCR2- CX3CR1hi) mouse monocytes correspond to human CD14hi CD16- and CD14+ CD16+ monocytes, respectively. Ly-6Chi cells selectively populate sites of experimentally induced inflammation while their Ly-6Clo counterparts can enter lymphoid and nonlymphoid tissues under homeostatic conditions. Monocyte heterogeneity suggests that tissue tropism, cellular differentiation and role in immunity may vary between subsets. We report that Ly-6Chi, but not Ly-6Clo, mouse monocytes actively accumulate in atheromata where they differentiate into macrophages (JCI, 2007, 117:195 ), Also, hypercholesterolemic mice show Ly-6Chi cell number doubling in the blood and spleen every month, a process that we have termed hypercholesterolemia-associated monocytosis (HAM) (JCI, 2007, 117:195 ).

Imaging technologies such as Single Photon Emission Computed Tomography/ X-ray Computed Tomography (SPECT/CT), now adapted for use in rodents, allow for dynamic, non-invasive, quantitative, in vivo assessment of cellular migration and accumulation. The dual modality system combines X-ray and gamma ray detection to generate 3D images of high sensitivity and resolution. We are utilizing this technology to study directly the recruitment and accumulation of monocytes and T cells in atherosclerotic lesions of hypercholesterolemic mice. These studies aim to better understand the role of leukocyte migration in disease progression and may form the basis of novel immunotherapeutic intervention strategies.

Figure5

3D reconstruction of SPECT/CT data depicting region of monocyte accumulation in vivo. 4 X 106 peripheral blood monocytes were labeled with 111-Indium-oxine (50 ┬ÁCi) and injected i.v. to 5-mo old ApoE KO mice. 5 d post injection, animals were anaesthetized and imaged on a X-SPECT/CT machine. SPECT and CT images were reconstructed and superimposed to generate a 3D image.