The macrophage (Mφ) foam cell in the atherosclerotic plaque microenvironment is subjected to cytokines and growth factors secreted by smooth muscle cells (SMCs), endothelial cells (ECs), platelets and lesional Mφ themselves. This thesis examines the effects of some of these soluble factors on a murine macrophage membrane molecule, the macrophage scavenger receptor (MSR), considered pivotal in foam cell formation and atherogenesis. Macrophage Colony-stimulating factor (MCSF) enhances MSR expression and functional activity (including MSR-dependent adhesion) in elicited peritoneal Mφ markedly and selectively. The T lymphocyte products, Th1 (interferon-gamma(IFN-γ)) and Th2 (chiefly interleukin-4 (IL-4)) cytokines, have divergent effects with IL-4 upregulating and IFN-γ either maintaining or downregulating MSR status. IL-4 induced MSR microheterogeneity is due to changes in N-linked glycosylation, specifically sialylation and may be physiologically significant. In contrast to interleukin-10 (IL-10), transforming growth factor-beta (TGF-β) inhibits MSR upregulation, also when produced endogenously. TGF-β is as potent an inhibitor of MSR function as M-CSF is a stimulator. A cleaved truncated soluble form of MSR which lacks the cytoplasmic domain is present, by immunochemical assays, in culture supernatants. M-CSF increases soluble MSR release in vitro which is functionally active. Following upregulation of MSR surface expression in transfected CHO cells by prolonged culture, a modest MSR-dependent contribution to adhesion becomes apparent. To determine a possible adhesionpromoting region in the MSR, the binding site of mAb 2F8 was mapped using a series of MSR truncation mutants, and localized to residues 183 to 197 in the proximal cchelical coiled-coil domain. Morphological evidence, obtained by confocal and electron microscopy, supports an adhesion role for the MSR in primary Mφ and transfected CHO cells. MSR expression is prominently directed to the adherent surface and its distribution is restricted to cellular contact areas with the substratum. Organs and atherosclerotic lesions from mice deficient in M-CSF (osteopetrotic) and apolipoprotein E were examined to determine the effects of M-CSF on Mφ phenotype (including MSR expression) and lesion development in vivo. Though severely hypercholesterolemic, doubly deficient mice are protected against atherosclerosis and exhibit fewer Mφ and low MSR expression on remaining M-CSF independent populations. Prominent hepatic lipid accumulation suggests a crucial M-CSF dependent role for Kupffer cells in lipoprotein uptake, transfer to hepatocytes and biliary excretion of cholesterol. Regulation of MSR activity may therefore be important for the recruitment of Mφ into the arterial wall and, at the post-endothelial stage, to anchor Mφ at specific locations, thus favouring foam cell formation.

Macrophage activation plays a crucial role in regulating adipose tissue inflammation and is a major contributor to the pathogenesis of obesity-associated cardiovascular diseases. On various types of stimuli, macrophages respond with either classic (M1) or alternative (M2) activation. M1- and M2-mediated signaling pathways and corresponding cytokine production profiles are not completely understood. The discovery of microRNAs provides a new opportunity to understand this complicated but crucial network for macrophage activation and adipose tissue function. We have examined the activity of microRNA-223 (miR-223) and its role in controlling macrophage functions in adipose tissue inflammation and systemic insulinresistance. miR-223-/- mice on a high-fat diet exhibited an increased severity of systemic insulin resistance compared with wild-type mice that was accompanied by a marked increase in adipose tissue inflammation. The specific regulatory effects of miR-223 in myeloid cell-mediated regulation of adipose tissue inflammation and insulin resistance were then confirmed by transplantation analysis. Moreover, using bone marrow-derived macrophages, we demonstrated that miR-223 is a novel regulator of macrophage polarization, which suppresses classic pro-inflammatory pathways and enhances the alternative anti-inflammatory responses. In addition, we identified Pknox1 as a genuine miR-223 target gene and an essential regulator for macrophage polarization. For the first time, this study demonstrates that miR-223 acts to inhibit Pknox 1,suppressing pro-inflammatory activation of macrophages; thus, it is a crucial regulator of macrophage polarization and protects against diet-induced adipose tissue inflammatory response and systemic insulin resistance.

Thesis (Ph. D.)--University of Hong Kong, 2007. / Also available in print.

Diss. (sammanfattning) Umeå : Univ., 2004. / Härtill 5 uppsatser.

Thesis (M.S.)--University of Toledo, 2007. / "In partial fulfillment of the requirements for the degree of Master of Science in Biomedical Sciences." Title from title page of PDF document. A role for iglC in the growth and persistence of Francisella tularensis within macrophages. Bibliography: p. 78-85

Thesis (Ph. D.)--University of Nevada, Reno, 2005. / "May 2005." Includes bibliographical references. Online version available on the World Wide Web.

Thesis (Ph. D.)--University of Virginia, 2008. / Title from title page. Includes bibliographical references. Also available online through Digital Dissertations.

Thesis (Ph. D.)--Case Western Reserve University, 2008. / [School of Medicine] Department of Pathology. Includes bibliographical references.

Thèse (M.Sc.)--Université Laval, 2007. / Bibliogr.: f. 49-64. Publié aussi en version électronique dans la Collection Mémoires et thèses électroniques.

Thesis (M.S.)--Rochester Institute of Technology, 1984. / Typescript. Includes bibliographical references (leaves 32-35).