title: Myeloid-derived suppressor cells are involved in lysosomal acid lipase deficiency-induced endothelial cell dysfunctions.
abstract: 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.
authors.affiliation: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202;
authors.forename: Ting
authors.initials: T
authors.lastname: Zhao
authors.affiliation: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202;
authors.forename: Xinchun
authors.initials: X
authors.lastname: Ding
authors.affiliation: 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.
authors.forename: Hong
authors.initials: H
authors.lastname: Du
authors.affiliation: 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.
authors.forename: Cong
authors.initials: C
authors.lastname: Yan
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000096:biosynthesis; D017209:Apoptosis / Q000276:immunology; D001854:Bone Marrow Cells / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000096:biosynthesis; D042783:Endothelial Cells / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000235:genetics; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D002787:Sterol Esterase / Q000172:deficiency / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D057705:Transendothelial and Transepithelial Migration / Q000276:immunology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics; D015223:Wolman Disease / Q000235:genetics / Q000276:immunology*
chemical_list: D000950:Antigens, Ly; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; C480309:Ly6G antigen, mouse; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D017382:Reactive Oxygen Species; C546843:mTOR protein, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2; D058570:TOR Serine-Threonine Kinases; D002787:Sterol Esterase; C505054:lysosomal acid lipase, mouse