Blockade of Tim-1 and Tim-4 enhances atherosclerosis in low-density lipoprotein receptor-deficient mice
(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.
(Less)
- author
- publishing date
- 2016-03-01
- 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
- 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
- 2024-04-17 04:47:16
@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}},
keywords = {{apoptosis; atherosclerosis; inflammation; macrophage; T cells; Tim}},
language = {{eng}},
month = {{03}},
number = {{3}},
pages = {{456--465}},
publisher = {{Lippincott Williams & Wilkins}},
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}},
}