title: Neutrophil Elastase Regulates Emergency Myelopoiesis Preceding Systemic Inflammation in Diet-induced Obesity.
abstract: Inflammation plays a significant role in the development of obesity-related complications, but the molecular events that initiate and propagate such inflammation remain unclear. Here, we report that mice fed a high-fat diet (HFD) for as little as 1-3 days show increased differentiation of myeloid progenitors into neutrophils and monocytes but reduced B lymphocyte production in the bone marrow. Levels of neutrophil elastase (NE) and the nuclear factors CCAAT/enhancer-binding protein α (C/EBPα) and growth factor-independent 1 (GFI-1) are elevated in hematopoietic stem and progenitor cells from HFD-fed mice, but mice lacking either NE or C/EBPα are resistant to HFD-induced myelopoiesis. NE deletion increases expression of the inhibitory isoform of p30 C/EBPα, impairs the transcriptional activity of p42 C/EBPα, and reduces expression of the C/EBPα target gene GFI-1 in hematopoietic stem and progenitor cells, suggesting a mechanism by which NE regulates myelopoiesis. Furthermore, NE deletion prevents HFD-induced vascular leakage. Thus, HFD feeding rapidly activates bone marrow myelopoiesis through the NE-dependent C/EBPα-GFI-1 pathway preceding vascular damage and systemic inflammation.
authors.affiliation: From the Department of Pharmacology and Experimental Therapeutics and.|Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts 02118.
authors.forename: Jun-Yuan
authors.initials: JY
authors.lastname: Huang
authors.affiliation: From the Department of Pharmacology and Experimental Therapeutics and.|Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts 02118.
authors.forename: Qiong Lin
authors.initials: QL
authors.lastname: Zhou
authors.affiliation: From the Department of Pharmacology and Experimental Therapeutics and.|Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts 02118.
authors.forename: Chun-Hong
authors.initials: CH
authors.lastname: Huang
authors.affiliation: From the Department of Pharmacology and Experimental Therapeutics and.|Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts 02118.
authors.forename: Ye
authors.initials: Y
authors.lastname: Song
authors.affiliation: From the Department of Pharmacology and Experimental Therapeutics and.|Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts 02118.
authors.forename: Andria G
authors.initials: AG
authors.lastname: Sharma
authors.affiliation: From the Department of Pharmacology and Experimental Therapeutics and.|Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts 02118.
authors.forename: Zhangping
authors.initials: Z
authors.lastname: Liao
authors.affiliation: From the Department of Pharmacology and Experimental Therapeutics and.|Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts 02118.
authors.forename: Kavin
authors.initials: K
authors.lastname: Zhu
authors.affiliation: From the Department of Pharmacology and Experimental Therapeutics and.|Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts 02118.
authors.forename: Miles W
authors.initials: MW
authors.lastname: Massidda
authors.affiliation: From the Department of Pharmacology and Experimental Therapeutics and.|Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts 02118.
authors.forename: Ryan R
authors.initials: RR
authors.lastname: Jamieson
authors.affiliation: the Harvard Stem Cell Institute, Boston, Massachusetts 02115, and.
authors.forename: Jun-Yuan
authors.initials: JY
authors.lastname: Zhang
authors.affiliation: the Harvard Stem Cell Institute, Boston, Massachusetts 02115, and.|the Cancer Science Institute, National University of Singapore, Singapore 117599.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Tenen
authors.affiliation: From the Department of Pharmacology and Experimental Therapeutics and zyjiang@bu.edu.|Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts 02118.
authors.forename: Zhen Y
authors.initials: ZY
authors.lastname: Jiang
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D001853:Bone Marrow / Q000276:immunology / Q000473:pathology; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics / Q000276:immunology; D002199:Capillary Permeability; D059305:Diet, High-Fat / Q000009:adverse effects*; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006412:Hematopoietic Stem Cells / Q000276:immunology / Q000473:pathology; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000503:physiopathology*; D019272:Leukocyte Elastase / Q000235:genetics / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000276:immunology / Q000473:pathology; D038042:Myelopoiesis; D009504:Neutrophils / Q000276:immunology / Q000473:pathology; D009765:Obesity / Q000209:etiology* / Q000235:genetics / Q000276:immunology / Q000503:physiopathology*
chemical_list: D022763:CCAAT-Enhancer-Binding Protein-alpha; D019272:Leukocyte Elastase
keywords: bone marrow; inflammation; metabolic disease; myelopoiesis; neutrophil; neutrophil elastase; obesity; systemic inflammation; vascular leakage