Evidence map›Paper›PMID 26821944›Full record

ArticleArteriosclerosis, thrombosis, and vascular biology2016

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

Amanda C Foks, Daniel Engelbertsen, Felicia Kuperwaser, Noah Alberts-Grill, Ayelet Gonen, Joseph L Witztum, James Lederer, Petr Jarolim, Rosemarie H DeKruyff, Gordon J Freeman and 1 more

Open access · greenAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Arteriosclerosis, thrombosis, and vascular biology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.

0numbers the graph read from it
0cells of the map it votes in
34citing papers in PubMed
5.1field-weighted citation impact, top 4% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

34 citing papers in PubMed, 64 citations in OpenAlex.

  1. Mechanism of efferocytosis in atherosclerosis.Journal of molecular medicine (Berlin, Germany) · 2024
    Review
  2. Review
  3. Review
  4. Review
  5. Article
  6. Article
  7. Article
  8. Review
  9. Article
  10. Article
  11. Role of Tim4 in the regulation of ABCA1Nature communications · 2021
    Article
  12. Article
  13. Review
  14. Article
  15. Nasal Microbiota Modifies the Effects of Particulate Air Pollution on Plasma Extracellular Vesicles.International journal of environmental research and public health · 2020
    Article
  16. Tim-4 in Health and Disease: Friend or Foe?Frontiers in immunology · 2020
    Review
  17. Article
  18. Review
  19. Review
  20. International journal of medical sciences · 2019
    Observational
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

11 authors at 2 institutions in 1 country.

Amanda C FoksFrom 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.).
Daniel EngelbertsenFrom 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.).
Felicia KuperwaserFrom 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.).
Noah Alberts-GrillFrom 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.).
Ayelet GonenFrom 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.).
Joseph L WitztumFrom 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.).
James LedererFrom 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.).
Petr JarolimFrom 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.).
Rosemarie H DeKruyffFrom 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.).
Gordon J FreemanFrom 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.).
Andrew H LichtmanFrom 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.
University of California, San Diego · USStanford University · US

Funding

NUCLEAR FACTOR KAPPA BETA AND THE INITIATION OF THE ATHEROSCLEROTIC LESIONP50HL056985 · NHLBI · BRIGHAM AND WOMEN'S HOSPITAL · PI GIMBRONE, MICHAEL A · 1997 to 2006
$14.1M
TIM recognition of phosphatidylserine regulates innate and adaptive immunityP01AI054456 · NIAID · STANFORD UNIVERSITY · PI FREEMAN, GORDON JAMES · 2003 to 2014
$12.8M
Regulation of T Cell Responses in AtherosclerosisR01HL087282 · NHLBI · BRIGHAM AND WOMEN'S HOSPITAL · PI LICHTMAN, ANDREW H · 2007 to 2015
$4.0M
TIM recognition of PtdSer on apoptotic cells and the regulation of immunityR01AI089955 · NIAID · DANA-FARBER CANCER INST · PI DEKRUYFF, ROSEMARIE H, FREEMAN, GORDON JAMES · 2010 to 2014
$2.1M
Protection of the Heart by PD-1 and PD-L1R01HL121363 · NHLBI · BRIGHAM AND WOMEN'S HOSPITAL · PI LICHTMAN, ANDREW H, SHARPE, ARLENE H. · 2014 to 2017
$1.7M
NHLBI NIH HHS HL087282NHLBI NIH HHS P50 HL056985NHLBI NIH HHS R01 HL087282NHLBI NIH HHS R01 HL121363NIAID NIH HHS P01 AI054456NIAID NIH HHS P01AI054456NIAID NIH HHS R01 AI089955NIAID NIH HHS R01AI089955
6 · The paper itself

Abstract

objectiveT 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

resultsldlr(-/-) 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%.

conclusionsBlockade 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.

Indexed as

AnimalsAntibodies, MonoclonalAortic DiseasesApoptosisAtherosclerosisCD4-Positive T-LymphocytesCell ProliferationCells, CulturedCoculture TechniquesDiet, High-FatDisease Models, AnimalFemaleHepatitis A Virus Cellular Receptor 1Lipoproteins, LDLLymphocyte ActivationMacrophagesAntibodies, MonoclonalHavcr1 protein, mouseHepatitis A Virus Cellular Receptor 1Lipoproteins, LDLMembrane Proteinsoxidized low density lipoproteinReceptors, LDLTIM-4 protein, mouseapoptosisatherosclerosisinflammationmacrophageT cellsTim

Identifiers

PMID26821944
PMCPMC4853762
OpenAlexW2261389324

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.