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Tytuł pozycji:

TLR4 (Toll-Like Receptor 4)-Dependent Signaling Drives Extracellular Catabolism of LDL (Low-Density Lipoprotein) Aggregates.

Tytuł:
TLR4 (Toll-Like Receptor 4)-Dependent Signaling Drives Extracellular Catabolism of LDL (Low-Density Lipoprotein) Aggregates.
Autorzy:
Singh RK; From the Department of Biochemistry, Weill Cornell Medical College, New York, NY (R.K.S., A.S.H., A.A., V.C.B.-L., I.G., H.F.C., F.R.M.).
Haka AS; From the Department of Biochemistry, Weill Cornell Medical College, New York, NY (R.K.S., A.S.H., A.A., V.C.B.-L., I.G., H.F.C., F.R.M.).
Asmal A; From the Department of Biochemistry, Weill Cornell Medical College, New York, NY (R.K.S., A.S.H., A.A., V.C.B.-L., I.G., H.F.C., F.R.M.).
Barbosa-Lorenzi VC; From the Department of Biochemistry, Weill Cornell Medical College, New York, NY (R.K.S., A.S.H., A.A., V.C.B.-L., I.G., H.F.C., F.R.M.).
Grosheva I; From the Department of Biochemistry, Weill Cornell Medical College, New York, NY (R.K.S., A.S.H., A.A., V.C.B.-L., I.G., H.F.C., F.R.M.).
Chin HF; From the Department of Biochemistry, Weill Cornell Medical College, New York, NY (R.K.S., A.S.H., A.A., V.C.B.-L., I.G., H.F.C., F.R.M.).
Xiong Y; Vascular Biology Program, Boston Children's Hospital and Department of Surgery, Harvard Medical School, Boston, MA (Y.X., T.H.).; Current address: Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY (Y.X.).
Hla T; Vascular Biology Program, Boston Children's Hospital and Department of Surgery, Harvard Medical School, Boston, MA (Y.X., T.H.).
Maxfield FR; From the Department of Biochemistry, Weill Cornell Medical College, New York, NY (R.K.S., A.S.H., A.A., V.C.B.-L., I.G., H.F.C., F.R.M.).
Źródło:
Arteriosclerosis, thrombosis, and vascular biology [Arterioscler Thromb Vasc Biol] 2020 Jan; Vol. 40 (1), pp. 86-102. Date of Electronic Publication: 2019 Oct 10.
Typ publikacji:
Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
Język:
English
Imprint Name(s):
Publication: 1998- : Baltimore, Md. : Lippincott Williams & Wilkins
Original Publication: Dallas, TX : American Heart Association, c1995-
MeSH Terms:
Aorta, Thoracic/*metabolism
Atherosclerosis/*metabolism
Extracellular Fluid/*metabolism
Foam Cells/*metabolism
Lipoproteins, LDL/*metabolism
Toll-Like Receptor 4/*metabolism
Animals ; Aorta, Thoracic/pathology ; Atherosclerosis/pathology ; Cells, Cultured ; Disease Models, Animal ; Female ; Flow Cytometry ; Foam Cells/pathology ; Immunoblotting ; Mice ; Mice, Knockout ; Signal Transduction
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Grant Information:
P30 CA008748 United States CA NCI NIH HHS; R01 HL093324 United States HL NHLBI NIH HHS; R35 HL135821 United States HL NHLBI NIH HHS; R37 DK027083 United States DK NIDDK NIH HHS
Contributed Indexing:
Keywords: atherosclerosis; bone marrow; foam cells; lysosomes; macrophage
Substance Nomenclature:
0 (Lipoproteins, LDL)
0 (Toll-Like Receptor 4)
Entry Date(s):
Date Created: 20191011 Date Completed: 20200420 Latest Revision: 20210101
Update Code:
20240104
PubMed Central ID:
PMC6928397
DOI:
10.1161/ATVBAHA.119.313200
PMID:
31597445
Czasopismo naukowe
Objective: Aggregation and modification of LDLs (low-density lipoproteins) promote their retention and accumulation in the arteries. This is a critical initiating factor during atherosclerosis. Macrophage catabolism of agLDL (aggregated LDL) occurs using a specialized extracellular, hydrolytic compartment, the lysosomal synapse. Compartment formation by local actin polymerization and delivery of lysosomal contents by exocytosis promotes acidification of the compartment and degradation of agLDL. Internalization of metabolites, such as cholesterol, promotes foam cell formation, a process that drives atherogenesis. Furthermore, there is accumulating evidence for the involvement of TLR4 (Toll-like receptor 4) and its adaptor protein MyD88 (myeloid differentiation primary response 88) in atherosclerosis. Here, we investigated the role of TLR4 in catabolism of agLDL using the lysosomal synapse and foam cell formation. Approach and Results: Using bone marrow-derived macrophages from knockout mice, we find that TLR4 and MyD88 regulate compartment formation, lysosome exocytosis, acidification of the compartment, and foam cell formation. Using siRNA (small interfering RNA), pharmacological inhibition and knockout bone marrow-derived macrophages, we implicate SYK (spleen tyrosine kinase), PI3K (phosphoinositide 3-kinase), and Akt in agLDL catabolism using the lysosomal synapse. Using bone marrow transplantation of LDL receptor knockout mice with TLR4 knockout bone marrow, we show that deficiency of TLR4 protects macrophages from lipid accumulation during atherosclerosis. Finally, we demonstrate that macrophages in vivo form an extracellular compartment and exocytose lysosome contents similar to that observed in vitro for degradation of agLDL.
Conclusions: We present a mechanism in which interaction of macrophages with agLDL initiates a TLR4 signaling pathway, resulting in formation of the lysosomal synapse, catabolism of agLDL, and lipid accumulation in vitro and in vivo.

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