PMID- 25000979
OWN - NLM
STAT- MEDLINE
DCOM- 20141021
LR  - 20240102
IS  - 1550-6606 (Electronic)
IS  - 0022-1767 (Print)
IS  - 0022-1767 (Linking)
VI  - 193
IP  - 4
DP  - 2014 Aug 15
TI  - Myeloid-derived suppressor cells are involved in lysosomal acid lipase 
      deficiency-induced endothelial cell dysfunctions.
PG  - 1942-53
LID - 10.4049/jimmunol.1301941 [doi]
AB  - The underlying mechanisms that lysosomal acid lipase (LAL) deficiency causes 
      infiltration of myeloid-derived suppressor cells (MDSCs) in multiple organs and 
      subsequent inflammation remain incompletely understood. Endothelial cells (ECs), 
      lining the inner layer of blood vessels, constitute barriers regulating 
      leukocytes transmigration to the site of inflammation. Therefore, we hypothesized 
      that ECs are dysfunctional in LAL-deficient (lal(-/-)) mice. We found that 
      Ly6G(+) cells transmigrated more efficiently across lal(-/-) ECs than wild-type 
      (lal(+/+)) ECs, which were associated with increased levels of PECAM-1 and MCP-1 
      in lal(-/-) ECs. In addition, lal(-/-) ECs showed enhanced migration and 
      proliferation, decreased apoptosis, but impaired tube formation and angiogenesis. 
      lal(-/-) ECs also suppressed T cell proliferation in vitro. Interestingly, 
      lal(-/-) Ly6G(+) cells promoted in vivo angiogenesis (including a tumor model), 
      EC tube formation, and proliferation. Finally, the mammalian target of rapamycin 
      (mTOR) pathway was activated in lal(-/-) ECs, and inhibition of mTOR reversed EC 
      dysfunctions, including decreasing Ly6G(+) cell transmigration, delaying 
      migration, and relieving suppression of T cell proliferation, which was mediated 
      by decreasing production of reactive oxygen species. Our results indicate that 
      LAL regulates EC functions through interaction with MDSCs and modulation of the 
      mTOR pathway, which may provide a mechanistic basis for targeting MDSCs or mTOR 
      to rejuvenate EC functions in LAL deficiency-related diseases.
CI  - Copyright (c) 2014 by The American Association of Immunologists, Inc.
FAU - Zhao, Ting
AU  - Zhao T
AD  - Department of Pathology and Laboratory Medicine, Indiana University School of 
      Medicine, Indianapolis, IN 46202;
FAU - Ding, Xinchun
AU  - Ding X
AD  - Department of Pathology and Laboratory Medicine, Indiana University School of 
      Medicine, Indianapolis, IN 46202;
FAU - Du, Hong
AU  - Du H
AD  - Department of Pathology and Laboratory Medicine, Indiana University School of 
      Medicine, Indianapolis, IN 46202; Indiana University Melvin and Bren Simon Cancer 
      Center, Indiana University School of Medicine, Indianapolis, IN 46202; and 
      coyan@iupui.edu hongdu@iupui.edu.
FAU - Yan, Cong
AU  - Yan C
AD  - Department of Pathology and Laboratory Medicine, Indiana University School of 
      Medicine, Indianapolis, IN 46202; Indiana University Melvin and Bren Simon Cancer 
      Center, Indiana University School of Medicine, Indianapolis, IN 46202; and Center 
      for Immunobiology, Indiana University School of Medicine, Indianapolis, IN 46202 
      coyan@iupui.edu hongdu@iupui.edu.
LA  - eng
GR  - R01 CA138759/CA/NCI NIH HHS/United States
GR  - P30 CA082709/CA/NCI NIH HHS/United States
GR  - R01 HL087001/HL/NHLBI NIH HHS/United States
GR  - CA152099/CA/NCI NIH HHS/United States
GR  - CA138759/CA/NCI NIH HHS/United States
GR  - HL087001/HL/NHLBI NIH HHS/United States
GR  - R01 CA152099/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20140707
PL  - United States
TA  - J Immunol
JT  - Journal of immunology (Baltimore, Md. : 1950)
JID - 2985117R
RN  - 0 (Antigens, Ly)
RN  - 0 (Ccl2 protein, mouse)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Ly6G antigen, mouse)
RN  - 0 (Platelet Endothelial Cell Adhesion Molecule-1)
RN  - 0 (Reactive Oxygen Species)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.10.1 (Vascular Endothelial Growth Factor Receptor-2)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.1.1.13 (Sterol Esterase)
RN  - EC 3.1.1.13 (lysosomal acid lipase, mouse)
SB  - IM
MH  - Animals
MH  - Antigens, Ly/biosynthesis
MH  - Apoptosis/immunology
MH  - Bone Marrow Cells/immunology
MH  - CD4-Positive T-Lymphocytes/immunology
MH  - Cell Proliferation
MH  - Cells, Cultured
MH  - Chemokine CCL2/biosynthesis
MH  - Endothelial Cells/*immunology
MH  - Lymphocyte Activation/immunology
MH  - Macrophages/*immunology
MH  - Mice
MH  - Mice, Knockout
MH  - Neovascularization, Physiologic/genetics
MH  - Platelet Endothelial Cell Adhesion Molecule-1/biosynthesis/genetics
MH  - RNA Interference
MH  - Reactive Oxygen Species/metabolism
MH  - Sterol Esterase/deficiency/genetics
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors/genetics/*immunology
MH  - Transendothelial and Transepithelial Migration/*immunology
MH  - Vascular Endothelial Growth Factor Receptor-2/genetics
MH  - Wolman Disease/genetics/*immunology
PMC - PMC4119579
MID - NIHMS605985
EDAT- 2014/07/09 06:00
MHDA- 2014/10/22 06:00
PMCR- 2015/08/15
CRDT- 2014/07/09 06:00
PHST- 2014/07/09 06:00 [entrez]
PHST- 2014/07/09 06:00 [pubmed]
PHST- 2014/10/22 06:00 [medline]
PHST- 2015/08/15 00:00 [pmc-release]
AID - jimmunol.1301941 [pii]
AID - 10.4049/jimmunol.1301941 [doi]
PST - ppublish
SO  - J Immunol. 2014 Aug 15;193(4):1942-53. doi: 10.4049/jimmunol.1301941. Epub 2014 
      Jul 7.