2. Academic Validation
  3. Blockade of Tim-1 and Tim-4 Enhances Atherosclerosis in Low-Density Lipoprotein Receptor-Deficient Mice

Blockade of Tim-1 and Tim-4 Enhances Atherosclerosis in Low-Density Lipoprotein Receptor-Deficient Mice

  • Arterioscler Thromb Vasc Biol. 2016 Mar;36(3):456-65. doi: 10.1161/ATVBAHA.115.306860.
Amanda C Foks 1,  Daniel Engelbertsen 1,  Felicia Kuperwaser 1,  Noah Alberts-Grill 1,  Ayelet Gonen 1,  Joseph L Witztum 1,  James Lederer 1,  Petr Jarolim 1,  Rosemarie H DeKruyff 1,  Gordon J Freeman 1,  Andrew H Lichtman 2
Affiliations

Affiliations

  • 1 From the Department of Pathology (A.C.F., D.E., F.K., N.A.-G., P.J., A.H.L.) and Department of Surgery (J.L.), Harvard Medical School, Brigham and Women's Hospital, Boston, MA; Department of Medicine, University of California, San Diego, La Jolla (A.G., J.L.W.); Department of Medicine, Stanford University, Stanford, CA (R.H.D.); and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA (G.J.F.).
  • 2 From the Department of Pathology (A.C.F., D.E., F.K., N.A.-G., P.J., A.H.L.) and Department of Surgery (J.L.), Harvard Medical School, Brigham and Women's Hospital, Boston, MA; Department of Medicine, University of California, San Diego, La Jolla (A.G., J.L.W.); Department of Medicine, Stanford University, Stanford, CA (R.H.D.); and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA (G.J.F.). alichtman@partners.org.
PMID: 26821944 DOI: 10.1161/ATVBAHA.115.306860
Abstract

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.

Keywords

T cells; Tim; apoptosis; atherosclerosis; inflammation; macrophage.

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