CLINTON ROBBINS, Ph.D.
Laboratory Medicine and Pathology
University of Toronto
Scientist, Toronto General Research Institute
University Health Network
Keywords: atherosclerosis, inflammation, macrophage, proliferation, immunity
A quarter of all deaths in Canada are caused by complications associated with cardiovascular
disease. The main cause of vascular disease is atherosclerosis, or build-up of plaque in the
arteries. Atherosclerosis is an inflammatory disease. One subset of inflammatory cells,
macrophages, play an important role in atherosclerosis progression. How these cells gather in
plaques, however, is not clear. Macrophages can appear in plaques through recruitment of their
monocyte precursors from the bloodstream. Our recently published data shows macrophages also
proliferate or divide locally within the plaque.
(i) Investigating the role of lesional macrophage proliferation in atherosclerosis. Which process
- monocyte influx or macrophage proliferation - is more important? What are the mechanisms that drive proliferation? How does the balance between the two processes change with co-morbidities and treatment? Does one process influence the other? Which of the two is the better therapeutic target? The answers to these question are likely to identify new therapeutic targets in treating atherosclerosis.
(ii) Determining the contribution of embryonic- versus bone marrow-derived macrophages in atherosclerosis. Some macrophages develop from hematopoietic stem cells, while others develop prior to birth and independent of the bone marrow. We ask the important question whether functional differences exist between these different macrophage populations and to what extent each population contributes to disease.
(iii) Determining the molecular mechanisms that regulate macrophage accumulation in atherosclerosis. In addition to growth factors, hematopoiesis is tightly controlled at the transcriptional level. One such transcription factor, c-Myb, has been demonstrated to play an important role in the survival, proliferation, and differentiation of hematopoietic cells. We are currently studying the role of c-Myb in regulating inflammation in atherosclerosis.
- Swirski FK, Hilgendorf I, Robbins CS. From proliferation to proliferation: monocyte lineage comes full circle. Seminars in Immunopathology. In press.
- Robbins CS*, Hilgendorf I*, Weber GF, Theurl I, Iwamoto Y, Figueiredo JL, Gorbatov R, Sukhova GK, Gerhardt LM, Smyth D, Zavitz CC, Shikatani EA, Parsons M, Rooijen NV, Lin HY, Husain M, Libby P, Nahrendorf M, Weissleder R, Swirski FK. Local proliferation dominates lesional macrophage accumulation in atherosclerosis. Nat Med. 2013 Sep;19(9):1166-72. doi: 10.1038/nm.3258. Epub 2013 Aug 11.
- Dutta P*, Courties G*, Wei Y, Leuschner F, Gorbatov R, Robbins C.S., Iwamoto Y, Thompson B, Carlson A, Heidt T, Majmudar M, Lasitschka F, Etzrodt M, Waterman P, Waring M, Chicoine A, Laan A, Niessen H, Piek J, Rubin B, Butany J, Stone J, Katus H, Murphy S, Morrow D, Sabatine M, Vinegoni C, Moskowitz M, Pittet M, Libby P, Lin C, Swirski F, Weissleder R, Nahrendorf M. Myocardial infarction accelerates atherosclerosis. Nature, 2012 Jul 19;487(7407):325-9.
- Robbins, C.S.*, Rauch, P.J.*, Chudnovskiy, A.*, Weber, G.F., Etzrodt, M., Hilgendorf, I., Tiglao, E., Figueiredo, J.L., Iwamoto, Y., Theurl, I., Gorbatov, R., Waring, M.T., Chicoine, A.T., Mouded, M., Pittet, M.J., Nahrendorf, M., Weissleder, R., Swirski, F.K. Innate response activator B cells protect against microbial sepsis. Science. Feb 3;335(6068):597-601. Jan 12. [Epub ahead of print].
- Leuschner F., Rauch, P.J., Ueno, T., Gorbatov, R., Marinelli, B., Lee, W.W., Dutta, P., Wei, Y., Robbins, C.S., Iwamoto, Y., Brena Sena, Aleksey Chudnovskiy, Peter Panizzi, Edmund Keliher, John M. Higgins, Peter Libby, Michael A. Moskowitz, Mikael J. Pittet, Filip K. Swirski, Ralph Weissleder, Matthias Nahrendorf. Rapid monocyte kinetics in acute myocardial infarction are sustained by extramedullary monocytopoiesis. J. Exp. Med. 2012 Jan 3.
- Robbins, C.S.*, Chudnovskiy, A.*, Rauch, P.*, Figueiredo, J.L., Iwamoto, Y., Gorbatov, R., Etzrodt, M., Weber, G., Ueno, T., van Rooijen, N., Mulligan-Kehoe, M.J., Libby, P., Nahrendorf, M., Pittet, M., Weissleder, R., Swirski, F.K. Extramedullary hematopoiesis generates Ly6Chigh monocytes that infiltrate atherosclerotic lesions. Circulation. 2012 Jan 17;125(2):364-74. Epub 2011 Dec 5.
- Robbins, C.S., Swirski F.K. The multiple roles of monocyte subsets in steady state and inflammation. Cell Mol Life Sci. 2010. Aug; 67(16):2685-93. Epub 2010 May 1.
- Houghton AM*, Hartzell WO*, Robbins CS, Gomis-Rüth FX, Shapiro SD. Macrophage elastase kills bacteria within murine macrophages. Nature. 2009 Jul; 460(7255):637-41. Epub 2009 Jun 17.
- Robbins, C.S., Franco, F., Mouded, M., Cernadas, M., Shapiro, S.D., Cigarette smoke exposure impairs dendritic cell maturation and T cell proliferation in thoracic lymph nodes of mice. J. Immunol. 180(10):6623-8, 2008.