Bone marrow deficiency of mRNA decaying protein Tristetraprolin increases inflammation and mitochondrial ROS but reduces hepatic lipoprotein production in LDLR knockout mice
Fatma Saaoud,
Junfeng Wang,
Stephen Iwanowycz,
Yuzhen Wang,
Diego Altomare,
Ying Shao,
Jianguo Liu,
Perry J. Blackshear,
Susan M. Lessner,
E. Angela Murphy,
Hong Wang,
Xiaofeng Yang,
Daping Fan
Affiliations
Fatma Saaoud
Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC, 29209, USA; Centers for Inflammation, Translational & Clinical Lung Research, Departments of Microbiology and Immunology and Pharmacology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 14190, USA
Junfeng Wang
Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC, 29209, USA
Stephen Iwanowycz
Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC, 29209, USA
Yuzhen Wang
Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC, 29209, USA
Diego Altomare
Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC, 29208, USA
Ying Shao
Centers for Inflammation, Translational & Clinical Lung Research, Departments of Microbiology and Immunology and Pharmacology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 14190, USA
Jianguo Liu
Division of Infectious Diseases, Allergy and Immunology, Department of Internal Medicine, Saint Louis University School of Medicine, St. Louis, MO, 63104, USA
Perry J. Blackshear
Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, 27709, USA
Susan M. Lessner
Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC, 29209, USA
E. Angela Murphy
Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC, 29209, USA
Hong Wang
Metabolic Disease Research, Cardiovascular Research, and Thrombosis Research, Departments of Microbiology and Immunology, and Pharmacology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 14190, USA
Xiaofeng Yang
Centers for Inflammation, Translational & Clinical Lung Research, Departments of Microbiology and Immunology and Pharmacology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 14190, USA; Metabolic Disease Research, Cardiovascular Research, and Thrombosis Research, Departments of Microbiology and Immunology, and Pharmacology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 14190, USA; Corresponding author. Centers for Inflammation, Translational & Clinical Lung Research, Metabolic Disease Research and Cardiovascular Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 14190, USA.
Daping Fan
Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC, 29209, USA; Corresponding author. Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, 6439 Garners Ferry Road, Columbia, SC, 29209, USA.
Tristetraprolin (TTP), an mRNA binding and decaying protein, plays a significant role in controlling inflammation by decaying mRNAs encoding inflammatory cytokines such as TNFalpha. We aimed to test a hypothesis that TTP in bone marrow (BM) cells regulates atherogenesis by modulating inflammation and lipid metabolism through the modulation of oxidative stress pathways by TTP target genes. In a BM transplantation study, lethally irradiated atherogenic LDLR−/− mice were reconstituted with BM cells from either wild type (TTP+/+) or TTP knockout (TTP−/−) mice, and fed a Western diet for 12 weeks. We made the following observations: (1) TTP−/− BM recipients display a significantly higher systemic and multi-organ inflammation than TTP+/+ BM recipients; (2) BM TTP deficiency modulates hepatic expression of genes, detected by microarray, involved in lipid metabolism, inflammatory responses, and oxidative stress; (3) TTP−/− BM derived macrophages increase production of mitochondrial reactive oxygen species (mtROS); (4) BM-TTP−/− mice display a significant reduction in serum VLDL/LDL levels, and attenuated hepatic steatosis compared to controls; and (5) Reduction of serum VLDL/LDL levels offsets the increased inflammation, resulting in no changes in atherosclerosis. These findings provide a novel mechanistic insight into the roles of TTP-mediated mRNA decay in bone marrow-derived cells in regulating systemic inflammation, oxidative stress, and liver VLDL/LDL biogenesis.
