TABAS, IRA, M.D., Ph.D. Richard J. Stock Professor, Professor of Physiology & Cellular Biophysics, Medicine and Anatomy and CellBiology, Vice-Chairman of Research The cellular and molecular biology of macrophages during atherogenesis. Office: Presbyterian Hospital | 8th floor-east | Room 101B Telephone: 212.305.9430 Fax: 212.305.4834 Email:iat1@columbia.edu Tabas Lab

Current Research

The Tabas laboratory utilizes cell-culture models and induced mutant mice to explore areas of macrophage cellular and molecular biology that are pertinent to the development of atherosclerosis. A major focus of the laboratory is the molecular and cellular mechanisms and consequences resulting from macrophage apoptosis and from the phagocytic clearance of apoptotic cells, particularly in advanced atherosclerotic lesions. We have elucidated a multi-hit model of macrophage apoptosis that involves an ER stress pathway known as the Unfolded Protein Response (UPR). The key distal UPR effector responsible for cholesterol-induced macrophage death is the molecule CHOP (GADD153). CHOP enables apoptosis by promoting calcium release from the ER, which in turn induces a number of downstream apoptotic pathways through activation of calcium/calmodulin-dependent protein kinase II (CaMKII), STAT1, and NADPH oxidase. However, apoptosis requires a "second hit," and we have evidence that engagement of macrophage pattern recognition receptors (PRRs), notably toll-like receptors and scavenger receptors, play an important role in this regard. PRR engagement triggers apoptosis in ER-stressed macrophages by further promoting apoptotic signaling and suppressing compensatory cell survival signaling. We have developed a number of genetically altered mouse models to test these ideas in vivo. For example, deficiencies of CHOP, STAT1, or both SRA and CD36 (scavenger receptors) decrease advanced lesional macrophage apoptosis and plaque necrosis in Apoe-/- and/or Ldlr-/- mice. Moreover, in collaboration with Drs. Domenico Accili and Alan Tall at Columbia, we have shown the relevance of this overall pathway of macrophage apoptosis to advanced atherosclerosis in insulin resistant-states. Finally, the laboratory has in-vitro mechanistic studies and in-vivo mouse studies to explore the critical role of apoptotic cell clearance ("efferocytosis"), which we feel is a major determinant of whether macrophage death leads to the beneficial consequence of decreased cellularity or to the detrimental plaque-disrupting consequence of lesional necrosis. We discovered that a receptor called Mertk plays a critical role in the efferocytosis of apoptotic macrophages both in vitro and in advanced atherosclerotic lesions. The future goals of the laboratory are to pursue each of the areas in more depth both mechanistically and physiologically and to continually pinpoint areas of therapeutic potential, particularly in preventing the conversion of benign atherosclerotic lesions into disease-causing vulnerable plaques.

Selected Publications

Woo, C.W., Cui, D., Arrelano, J., Dorweiler,B., Harding, H., Fitzgerald, K.A., Ron, D., and Tabas, I. (2009) Adaptive suppression of the ATF4-CHOP branch of the unfolded protein response by toll-like receptor signaling.  In revision for Nature Cell Biol.

Devlin, C., Pipalia, N.H., Liao, X., Schuchman, E.H., Maxfield, F.R., Tabas, I. 2009. Marked improvement in lipid and protein trafficking in a lysosomal storage disease cell by correction of a secondary enzymatic defect.  In revision for Traffic.

Li, S., Sun, Y., Thorp, E., Jehle, A., Viswanathan, S., Kanter, J., Hasty, A., Bornfeldt, K., Tabas, I., Tall, A.R.  Defective phagocytosis of apoptotic cells by ob/ob peritoneal and atherosclerotic lesional macrophages:  reversal of defects by PPARg/d activation and fish oils.  Submitted for publication.

Seimon, T., Wang, Y., Kuriakose, G., Han, S., Senokuchi, T., Tall, A., Tabas, I. 2009. Deficiency of p38a in macrophages promotes apoptosis and plaque necrosis in advanced murine atherosclerotic lesions.  J. Clin. Invest. 119:886-898.

Sun, Y., Ishibashi, M., Seimon, T., Sharma, S.M., Fitzgerald, K.A., Samokhin, A.O., Wang. Y., Sayers, S., Aikawa, M., Jerome, G.W., Ostrowski, M.C., Bromme, D., Libby. P., Tabas, I., Welch, C.L., Tall, A.R. 2009. Free cholesterol accumulation in macrophage membranes activates Toll-like receptors, p38 MAP kinase and induces cathepsin K.  Circulation Res., 104:455-465.

Thorp, E., Li, G., Seimon, T.A., Kuriakose, G., Ron, D., Tabas, I. 2009. Reduced apoptosis and plaque necrosis in advanced atherosclerotic lesions of Apoe-/- and Ldlr-/- mice lacking CHOP. Cell Metabolism, 9:474-481.

Timmins, J., Ozcan, L., Seimon, T.A., Li, G., Malagelada, C., Backs, J., Backs, T., Bassel-Duby, R., Olson, E.N., Anderson, M.E., and Tabas, I. 2009. Calcium/calmodulin-dependent protein kinase II links endoplasmic reticulum stress with Fas and mitochondrial apoptosis pathways.  In revision for J. Clin. Invest..

Tam, C., Idone, V., Devlin, C., Tabas, I., Andrews, N.W. 2009. Exocytosis of acid sphingomyelinase upon cell injury triggers endocytosis and plasma membrane repair. In revision for Science.

Li, G., Mongillo, M., Chin, K-T., Harding, H., Ron, D., Marks, A.R., and Tabas, I. 2009. Role of ERO1a-mediated stimulation of inositol 1,4,5-triphosphate receptor activity in endoplasmic reticulum stress-induced apoptosis.  In revision for J. Cell Biol.

Manning-Tobin, J.J., Moore. K.J., Seimon, T.A., Bell, S.A., Sharuk, M., Alvarez-Leite, J.I., de Winther, M.P.J., Tabas, I., Freeman, M.W. 2009. Loss of SR-A and CD36 activity reduces atherosclerotic lesion complexity without abrogating foam cell formation in hyperlipidemic mice.  Arterio. Thromb. Vasc. Biol. 29:19-26.
             

Devlin, C.M., Leventhal, A.R., Kuriakose, G., Schuchman, E.H., Williams, K.J., Tabas, I. 2008. Acid sphingomyelinase promotes lipoprotein retention within early atheromata and accelerates lesion progression.  Arterio. Thromb. Vasc. Biol.  20:2607-2613.

Thorp, E., Li, Y., Bao, L., Yao, P.M., Kuriakose, G., Rong, J., Fisher, E.A., Tabas, I. 2008. Increased apoptosis in advanced atherosclerotic lesions of Apoe-/- mice lacking macrophage Bcl-2.  Arterio. Thromb. Vasc. Biol.  29:169-72.

Packard, R.R.S., Tabas, I., Libby, P., Lichtman, A.H. 2008. CD11c+ dendritic cells maintain antigen processing, presentation capabilities, and CD4+.  Circulation Res.103:965-973.

Li, Y., Zhang, Y., Dorweiler, B., Cui, D., Wang, T., Woo, C.W., Wolberger, C., Imai, S., Tabas, I. 2008. Extracellular Nampt protects macrophages from ER stress-induced apoptosis via a non-enzymatic interleukin-6/STAT3 signaling mechanism.  J. Biol. Chem. 283:34833–34843.

Thorp, E., Li, G., Kuriakose, G., Ron, D., and Tabas, I.  2008. Reduced apoptosis and plaque necrosis in advanced atherosclerotic lesions of Apoe-/- mice lacking CHOP.  Submitted for publication.

Senokuchi, T., Liang, C.P., Seimon, T.A., Han, S., Matsumoto, M., Paik, J.H., DePinho, R.A., Accili, D., Tabas, I., and Tall, A.R. 2008. FoxOs promote apoptosis of insulin resistant macrophages during cholesterol-induced ER stress.  Submitted for publication.

Iqbal, J., Dai, K., Seimon, T.A., Jungreis, R., Oyadomari, M., Ron, D., Tabas, I., and Hussain, M. 2008. IRE1β restricts chylomicron production by selectively degrading MTP mRNA.  In revision for Cell Metabolism.

Thorp, E., Cui, D., Kuriakose, G., and Tabas, I. 2008.  Mutation of the Mertk receptor promotes apoptotic cell accumulation and plaque necrosis in advanced atherosclerotic lesions of apolipoprotein E-deficient mice.  Submitted for publication. 

Lim, W., Timmins, J., Seimon, T.A., Sadler, A., Kolodgie, F., Virmani, R., Schindler, C., and Tabas, I. 2008. A pathway involving calcium/calmodulin-dependent protein kinase II and serine-phosphorylated Stat1 is critical for endoplasmic reticulum stress-dependent macrophage apoptosis.  A new component of the multi-hit model of macrophage death relevant to advanced atherosclerosis.  Circulation, In press. 

Klionsky, D., et al. 2008. Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes. Autophagy 4:2-25.

Li, Y., and Tabas, I. 2007. The inflammatory cytokine response of cholesterol-enriched macrophages is suppressed by stimulated pinocytosis. J. Leukoc. Biol. 81: 483–491. 

Tabas, I.  2007. Lipid and atherosclerosis. IN Biochemistry of Lipids, Lipoproteins, and Membranes (Vance, D.E. and Vance, J., eds.), Elsevier, Amsterdam.  5th Edition, In press.

Cui, D., Thorp, E., Li, Y., Wang, N., Yvan-Charvet, L., Tall, A.R., and Tabas, I.  2007.  Pivotal Advance:  Macrophages become resistant to cholesterol-induced death after phagocytosis of apoptotic cells.  J. Leukoc. Biol. 82:1040-50.

Bao, S., Li, Y., Leia, X., Wohltmanna, M., Bohrera, A., Ramanadhama, S., Tabas, I., and Turk, J.  2007. Attenuated free cholesterol loading-induced apoptosis but preserved phospholipid composition of peritoneal macrophages from mice that do not express group VIA phospholipase A2.  J. Biol. Chem. 282:27100-14.

Thorp, E., Kuriakose, G., Shah, Y.M., Gonzalez, F.J., and Tabas, I. 2007. Pioglitazone increases macrophage apoptosis and plaque necrosis in advanced atherosclerotic lesions of non-diabetic LDL receptor-null mice.  Circulation 116:2182-2190.

Tabas, I.  2007. Macrophage death, plaque necrosis, and insulin resistance.  Clin. Invest. Arterioscl. Suppl. 3, 53-55.

Tabas, I.  2007. Apoptosis and efferocytosis in mouse models of atherosclerosis. Current Drug Targets 8:1288-1296.

Tabas, I., Williams, K.J., Borén, J. 2007. Subendothelial lipoprotein retention as the initiating process in atherosclerosis. Update and therapeutic implications. Circulation 116:1832-44.

Tabas, I., Seimon, T., Arrelano, J., Li, Y., Forcheron, F., Cui, D., Han, S., Liang, C.P., Tall, A., Accili, D.  2007. The impact of insulin resistance on macrophage death pathways in advanced atherosclerosis.  IN Fatty Acids and Lipotoxicity in Obesity and Diabetes.  Novartis Foundation Symposium 286.  John Wiley & Sons, Ltd., Chichester, UK, pp. 99-112.

Tabas, I. 2007. Clinical and mechanistic links between diabetes and heart disease.  Medscape online:  http://www.medscape.com/viewarticle/566297.

Li, Y., Schwabe, R.F., DeVries-Seimon, T., Yao, P.M., Gerbod-Giannone, M.C., Tall, A.R., Davis, R.J., Flavell, R., Brenner, D.A., and Tabas, I. 2005. Free cholesterol-loaded macrophages are an abundant source of tumor necrosis factor-alpha and interleukin-6: model of NF-kappaB- and map kinase-dependent inflammation in advanced atherosclerosis. J Biol Chem. 280, 21763-72.

Tabas, I. 2005. Consequences and Therapeutic Implications of Macrophage Apoptosis in Atherosclerosis. The Importance of Lesion Stage and Phagocytic Efficiency. Arterioscler Thromb Vasc Biol.

Devries-Seimon, T., Li, Y., Yao, P.M., Stone, E., Wang, Y., Davis, R.J., Flavell, R., and Tabas, I. 2005. Cholesterol-induced macrophage apoptosis requires ER stress pathways and engagement of the type A scavenger receptor. J Cell Biol. 171, 61-73.

Maxfield, F.R., and Tabas, I. 2005.  Role of cholesterol and lipid organization in disease. Nature 438:36-45.

Li, Y., Ge, M., Ciani, L., Kuriakose, G., Westover, E.J., Dura, M., Covey, D.F., Freed, J.H., Maxfield, F.R., Lytton, J., and Tabas, I. 2004. Enrichment of endoplasmic reticulum with cholesterol inhibits sarcoplasmic-endoplasmic reticulum calcium ATPase-2b activity in parallel with increased order of membrane lipids: implications for depletion of endoplasmic reticulum calcium stores and apoptosis in cholesterol-loaded macrophages. J Biol Chem. 279, 37030-9. [view pdf]