Please use this identifier to cite or link to this item: http://scholarbank.nus.edu.sg/handle/10635/48360
Title: MECHANISMS CONTROLLING THE EXPANSION OF CDIIB+ DCS IN ATHEROSCLEROSIS
Authors: WONG HUI SIAN FIONA
Keywords: CD11b+ DCs; Atherosclerosis
Issue Date: 22-Aug-2013
Source: WONG HUI SIAN FIONA (2013-08-22). MECHANISMS CONTROLLING THE EXPANSION OF CDIIB+ DCS IN ATHEROSCLEROSIS. ScholarBank@NUS Repository.
Abstract: Atherosclerosis is the leading cause of mortality in many countries. It is an inflammatory disease of large and medium sized arteries characterized by hyperlipidemia. Dendritic cells (DCs) are one of the key players of the inflammatory brigade in atherosclerotic plaques and are known to accumulate in atherosclerosis. Past studies in atherosclerosis rely on classical markers such as CD11c and MHC class II to characterize DCs. However, recent identification of non-lymphoid tissue DC subsets based on additional markers such as CD11b and CD103 was introduced. Consequently, the need to distinguish DC populations in the atherosclerotic plaques arises. Based on the new classification, we managed to identify two different DC subsets, CD11b+ and CD103+ in the aorta at steady state, which localized at sites of predilection for atherosclerosis. Using the apoE-/- mouse model of atherosclerosis, we showed that both CD11b+ and CD103+ DCs expanded during disease, with CD11b+ DCs being the dominant population. Expansion of CD11b+ DCs was abrogated when we treated apoE-/- mice with a cholesterol-lowering drug, Ezetimibe. Since monocytosis is prominent in apoE-/- mice and was also abolished in Ezetimibe-treated apoE-/- mice, we hypothesized that monocytes may be the precursors of CD11b+ DCs. Supporting this hypothesis, adoptively transferred monocytes differentiated into CD11b+ DCs in the aortas of apoE-/- mice. Moreover, employing the use of a monocyte-derived cell marker CD64, we showed that the proportion of CD11b+ DCs expressing CD64 in apoE-/- mice was increased as compared to wild-type (WT) controls. For DC differentiation to occur, growth factors are essential to the process. When we investigated which growth factors were present in atherosclerotic plaques, we discovered that only granulocyte-macrophage colony-stimulating factor (GM-CSF) was highly expressed in atherosclerotic aorta compared to normal aorta. Interestingly, this over-expression of GM-CSF was only detected in atherosclerotic plaques and not found in the circulation and aorta-associated draining lymph node. Subsequently, we showed that neutralizing GM-CSF partially diminished monocytosis and CD11b+ DC accumulation, demonstrating that GM-CSF is required for the expansion of CD11b+ DCs. We have also explored other possible mechanisms such as proliferation, expansion of bone marrow progenitors and extramedullary hematopoiesis and discounted their role in CD11b+ DC accumulation. Next, we initiated a study to examine the function of CD11b+ DCs. CD11b+ DCs produce pro-inflammatory factors, tumor necrosis factor alpha (TNF-a) and inducible nitric oxide synthase (iNOS) which are known to be pathogenic in atherosclerosis. As one of the by-products of iNOS activity is peroxynitrite which results in protein nitration and alteration of protein function, we found that CD11b+ DCs localized with sites of nitration in atherosclerotic plaques. Likely, CD11b+ DCs have a pro-inflammatory role in atherosclerosis. According to our findings, we suggest that by targeting monocytosis and GM-CSF, we could devise therapeutic strategies for atherosclerosis treatment.
URI: http://scholarbank.nus.edu.sg/handle/10635/48360
Appears in Collections:Master's Theses (Open)

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