This research program focuses on the cell biology of inflammation and the roles of mononuclear leukocytes in inflammatory processes. Studies are proposed in three major areas: 1) Structure and function of macrophage plasma membranes with particular reference to mechanisms of phagocytosis and pinocytosis. We will compare the protein composition of the segment of macrophage membrane in contact with a ligand (IgG, complement or mannose-rich oligosaccharide) coated target vs membrane that is not in contact with such a target. To determine whether ligand binding alters membrane """"""""fluidity"""""""" we will examine the mobility of membrane proteins in these two domains. Studies are planned of the effects of Fc receptor ligation on Fc receptor synthesis and distribution within various intracellular and surface membrane compartments of macrophages. ATP in the extracellular fluid causes membrane depolarization and inhibition of phagocytosis, presumably by affecting the function of the cells' ecto-ATPase. We will study the possibility that this ATPase is an ATP driven ion pump. 2) Mechanisms of tumor immunity. We have found that coinjection of activated macrophages with B16 melanoma cells in syngeneic C57BL/6 mice does not inhibit tumorigenesis if the mice were pretreated with antithymocyte serum. Tumor formation occurs even though this melanoma induces a more profound mononuclear leukocyte response in antithymocyte-serum treated mice than in normal mice. Several lines of evidence suggest that natural killer cell-macrophage cooperation is required to eradicate this tumor. Studies are proposed to test this hypothesis and to identify the specific types of mononuclear leukocytes that are responsible for tumor rejection. The mechanisms by which mononuclear phagocytes recognize and kill tumor cells also will be studied. 3) Structure of the vascular endothelium and the mechanism of leukocyte emigration. We have developed a """"""""model"""""""" vessel wall composed of bovine endothelial cells cultured on human amnion. The endothelial cell layer is """"""""tight"""""""" to macromolecular tracers. We have begun studies of the mechanism by which polymorphonuclear leukocytes open the junctions between these endothelial cells. Studies also are proposed to search for endothelial cell membrane proteins that are specific for different segments of the vasculature (artery vs vein vs capillary) and to identify the proteins that are responsible for intercellular junction formation.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Experimental Immunology Study Section (EI)
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Columbia University (N.Y.)
Schools of Medicine
New York
United States
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Silverstein, Samuel C; Rabadan, Raul (2012) How many neutrophils are enough (redux, redux)? J Clin Invest 122:2776-9
Budhu, Sadna; Loike, John D; Pandolfi, Ashley et al. (2010) CD8+ T cell concentration determines their efficiency in killing cognate antigen-expressing syngeneic mammalian cells in vitro and in mouse tissues. J Exp Med 207:223-35
Reich-Slotky, Ronit; Kabbash, Christina A; Della-Latta, Phyllis et al. (2009) Gemfibrozil inhibits Legionella pneumophila and Mycobacterium tuberculosis enoyl coenzyme A reductases and blocks intracellular growth of these bacteria in macrophages. J Bacteriol 191:5262-71
Sethy-Coraci, Indra; Crock, Lara W; Silverstein, Samuel C (2005) PAF-receptor antagonists, lovastatin, and the PTK inhibitor genistein inhibit H2O2 secretion by macrophages cultured on oxidized-LDL matrices. J Leukoc Biol 78:1166-74
Berger, Miles; Budhu, Sadna; Lu, Emily et al. (2002) Different G(i)-coupled chemoattractant receptors signal qualitatively different functions in human neutrophils. J Leukoc Biol 71:798-806
Husemann, Jens; Loike, John D; Anankov, Roman et al. (2002) Scavenger receptors in neurobiology and neuropathology: their role on microglia and other cells of the nervous system. Glia 40:195-205
Husemann, J; Silverstein, S C (2001) Expression of scavenger receptor class B, type I, by astrocytes and vascular smooth muscle cells in normal adult mouse and human brain and in Alzheimer's disease brain. Am J Pathol 158:825-32
Loike, J D; Cao, L; Budhu, S et al. (2001) Blockade of alpha 5 beta 1 integrins reverses the inhibitory effect of tenascin on chemotaxis of human monocytes and polymorphonuclear leukocytes through three-dimensional gels of extracellular matrix proteins. J Immunol 166:7534-42
Husemann, J; Obstfeld, A; Febbraio, M et al. (2001) CD11b/CD18 mediates production of reactive oxygen species by mouse and human macrophages adherent to matrixes containing oxidized LDL. Arterioscler Thromb Vasc Biol 21:1301-5
Husemann, J; Loike, J D; Kodama, T et al. (2001) Scavenger receptor class B type I (SR-BI) mediates adhesion of neonatal murine microglia to fibrillar beta-amyloid. J Neuroimmunol 114:142-50

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