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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 LU ; Kuperwaser, Felicia ; Alberts-Grill, Noah ; Gonen, Ayelet ; Witztum, Joseph L. ; Lederer, James ; Jarolim, Petr ; Dekruyff, Rosemarie H. and Freeman, Gordon J. , et al. (2016) In Arteriosclerosis, Thrombosis, and Vascular Biology 36(3). p.456-465
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-/-... (More)

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.

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publishing date
type
Contribution to journal
publication status
published
keywords
apoptosis, atherosclerosis, inflammation, macrophage, T cells, Tim
in
Arteriosclerosis, Thrombosis, and Vascular Biology
volume
36
issue
3
pages
456 - 465
publisher
Lippincott Williams Wilkins Hagerstown, MD
external identifiers
  • scopus:84959512270
  • pmid:26821944
ISSN
1079-5642
DOI
10.1161/ATVBAHA.115.306860
language
English
LU publication?
no
id
ceff82b4-4a09-42c7-ad66-de16a195f074
date added to LUP
2020-02-02 16:56:30
date last changed
2020-05-26 05:38:59
@article{ceff82b4-4a09-42c7-ad66-de16a195f074,
  abstract     = {<p>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<sup>-/-</sup> 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<sup>+</sup>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.</p>},
  author       = {Foks, Amanda C. and Engelbertsen, Daniel and Kuperwaser, Felicia and Alberts-Grill, Noah and Gonen, Ayelet and Witztum, Joseph L. and Lederer, James and Jarolim, Petr and Dekruyff, Rosemarie H. and Freeman, Gordon J. and Lichtman, Andrew H.},
  issn         = {1079-5642},
  language     = {eng},
  month        = {03},
  number       = {3},
  pages        = {456--465},
  publisher    = {Lippincott Williams  Wilkins Hagerstown, MD},
  series       = {Arteriosclerosis, Thrombosis, and Vascular Biology},
  title        = {Blockade of Tim-1 and Tim-4 enhances atherosclerosis in low-density lipoprotein receptor-deficient mice},
  url          = {http://dx.doi.org/10.1161/ATVBAHA.115.306860},
  doi          = {10.1161/ATVBAHA.115.306860},
  volume       = {36},
  year         = {2016},
}