Blockade of Tim-1 and Tim-4 enhances atherosclerosis in low-density lipoprotein receptor-deficient mice

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Blockade of Tim-1 and Tim-4 enhances atherosclerosis in low-density lipoprotein receptor-deficient mice. / Foks, Amanda C.; Engelbertsen, Daniel; Kuperwaser, Felicia; Alberts-Grill, Noah; Gonen, Ayelet; Witztum, Joseph L.; Lederer, James; Jarolim, Petr; Dekruyff, Rosemarie H.; Freeman, Gordon J.; Lichtman, Andrew H.

In: Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 36, No. 3, 01.03.2016, p. 456-465.

Research output: Contribution to journalArticle

Harvard

Foks, AC, Engelbertsen, D, Kuperwaser, F, Alberts-Grill, N, Gonen, A, Witztum, JL, Lederer, J, Jarolim, P, Dekruyff, RH, Freeman, GJ & Lichtman, AH 2016, 'Blockade of Tim-1 and Tim-4 enhances atherosclerosis in low-density lipoprotein receptor-deficient mice', Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 36, no. 3, pp. 456-465. https://doi.org/10.1161/ATVBAHA.115.306860

APA

Foks, A. C., Engelbertsen, D., Kuperwaser, F., Alberts-Grill, N., Gonen, A., Witztum, J. L., Lederer, J., Jarolim, P., Dekruyff, R. H., Freeman, G. J., & Lichtman, A. H. (2016). Blockade of Tim-1 and Tim-4 enhances atherosclerosis in low-density lipoprotein receptor-deficient mice. Arteriosclerosis, Thrombosis, and Vascular Biology, 36(3), 456-465. https://doi.org/10.1161/ATVBAHA.115.306860

CBE

Foks AC, Engelbertsen D, Kuperwaser F, Alberts-Grill N, Gonen A, Witztum JL, Lederer J, Jarolim P, Dekruyff RH, Freeman GJ, Lichtman AH. 2016. Blockade of Tim-1 and Tim-4 enhances atherosclerosis in low-density lipoprotein receptor-deficient mice. Arteriosclerosis, Thrombosis, and Vascular Biology. 36(3):456-465. https://doi.org/10.1161/ATVBAHA.115.306860

MLA

Vancouver

Author

Foks, Amanda C. ; Engelbertsen, Daniel ; Kuperwaser, Felicia ; Alberts-Grill, Noah ; Gonen, Ayelet ; Witztum, Joseph L. ; Lederer, James ; Jarolim, Petr ; Dekruyff, Rosemarie H. ; Freeman, Gordon J. ; Lichtman, Andrew H. / Blockade of Tim-1 and Tim-4 enhances atherosclerosis in low-density lipoprotein receptor-deficient mice. In: Arteriosclerosis, Thrombosis, and Vascular Biology. 2016 ; Vol. 36, No. 3. pp. 456-465.

RIS

TY - JOUR

T1 - Blockade of Tim-1 and Tim-4 enhances atherosclerosis in low-density lipoprotein receptor-deficient mice

AU - Foks, Amanda C.

AU - Engelbertsen, Daniel

AU - Kuperwaser, Felicia

AU - Alberts-Grill, Noah

AU - Gonen, Ayelet

AU - Witztum, Joseph L.

AU - Lederer, James

AU - Jarolim, Petr

AU - Dekruyff, Rosemarie H.

AU - Freeman, Gordon J.

AU - Lichtman, Andrew H.

PY - 2016/3/1

Y1 - 2016/3/1

N2 - Objective - T cell immunoglobulin and mucin domain (Tim) proteins are expressed by numerous immune cells, recognize phosphatidylserine on apoptotic cells, and function as costimulators or coinhibitors. Tim-1 is expressed by activated T cells but is also found on dendritic cells and B cells. Tim-4, present on macrophages and dendritic cells, plays a critical role in apoptotic cell clearance, regulates the number of phosphatidylserine-expressing activated T cells, and is genetically associated with low low-density lipoprotein and triglyceride levels. Because these functions of Tim-1 and Tim-4 could affect atherosclerosis, their modulation has potential therapeutic value in cardiovascular disease. Approach and Results - ldlr-/- mice were fed a high-fat diet for 4 weeks while being treated with control (rat immunoglobulin G1) or anti-Tim-1 (3D10) or -Tim-4 (21H12) monoclonal antibodies that block phosphatidylserine recognition and phagocytosis. Both anti-Tim-1 and anti-Tim-4 treatments enhanced atherosclerosis by 45% compared with controls by impairment of efferocytosis and increasing aortic CD4+T cells. Consistently, anti-Tim-4-treated mice showed increased percentages of activated T cells and late apoptotic cells in the circulation. Moreover, in vitro blockade of Tim-4 inhibited efferocytosis of oxidized low-density lipoprotein-induced apoptotic macrophages. Although anti-Tim-4 treatment increased T helper cell (Th)1 and Th2 responses, anti-Tim-1 induced Th2 responses but dramatically reduced the percentage of regulatory T cells. Finally, combined blockade of Tim-1 and Tim-4 increased atherosclerotic lesion size by 59%. Conclusions - Blockade of Tim-4 aggravates atherosclerosis likely by prevention of phagocytosis of phosphatidylserine-expressing apoptotic cells and activated T cells by Tim-4-expressing cells, whereas Tim-1-associated effects on atherosclerosis are related to changes in Th1/Th2 balance and reduced circulating regulatory T cells.

AB - Objective - T cell immunoglobulin and mucin domain (Tim) proteins are expressed by numerous immune cells, recognize phosphatidylserine on apoptotic cells, and function as costimulators or coinhibitors. Tim-1 is expressed by activated T cells but is also found on dendritic cells and B cells. Tim-4, present on macrophages and dendritic cells, plays a critical role in apoptotic cell clearance, regulates the number of phosphatidylserine-expressing activated T cells, and is genetically associated with low low-density lipoprotein and triglyceride levels. Because these functions of Tim-1 and Tim-4 could affect atherosclerosis, their modulation has potential therapeutic value in cardiovascular disease. Approach and Results - ldlr-/- mice were fed a high-fat diet for 4 weeks while being treated with control (rat immunoglobulin G1) or anti-Tim-1 (3D10) or -Tim-4 (21H12) monoclonal antibodies that block phosphatidylserine recognition and phagocytosis. Both anti-Tim-1 and anti-Tim-4 treatments enhanced atherosclerosis by 45% compared with controls by impairment of efferocytosis and increasing aortic CD4+T cells. Consistently, anti-Tim-4-treated mice showed increased percentages of activated T cells and late apoptotic cells in the circulation. Moreover, in vitro blockade of Tim-4 inhibited efferocytosis of oxidized low-density lipoprotein-induced apoptotic macrophages. Although anti-Tim-4 treatment increased T helper cell (Th)1 and Th2 responses, anti-Tim-1 induced Th2 responses but dramatically reduced the percentage of regulatory T cells. Finally, combined blockade of Tim-1 and Tim-4 increased atherosclerotic lesion size by 59%. Conclusions - Blockade of Tim-4 aggravates atherosclerosis likely by prevention of phagocytosis of phosphatidylserine-expressing apoptotic cells and activated T cells by Tim-4-expressing cells, whereas Tim-1-associated effects on atherosclerosis are related to changes in Th1/Th2 balance and reduced circulating regulatory T cells.

KW - apoptosis

KW - atherosclerosis

KW - inflammation

KW - macrophage

KW - T cells

KW - Tim

U2 - 10.1161/ATVBAHA.115.306860

DO - 10.1161/ATVBAHA.115.306860

M3 - Article

C2 - 26821944

AN - SCOPUS:84959512270

VL - 36

SP - 456

EP - 465

JO - Arteriosclerosis, Thrombosis and Vascular Biology

JF - Arteriosclerosis, Thrombosis and Vascular Biology

SN - 1524-4636

IS - 3

ER -