Neutrophil Elastase Regulates Emergency Myelopoiesis Preceding Systemic Inflammation in Diet-induced Obesity*

  1. Zhen Y. Jiang‡,§4
  1. From the ‡Department of Pharmacology and Experimental Therapeutics and
  2. §Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts 02118,
  3. the Harvard Stem Cell Institute, Boston, Massachusetts 02115, and
  4. the ‖Cancer Science Institute, National University of Singapore, Singapore 117599
  1. ↵4 To whom correspondence should be addressed: Whitaker Cardiovascular Institute, Boston University School of Medicine, 700 Albany St., Boston, MA 02118. Tel.: 617-638-4847; E-mail: zyjiang{at}bu.edu.

  1. ↵1 Both authors contributed equally to this work.

  2. Edited by Dennis R. Voelker

  • ↵2 Present address: Nanchang University Medical Center, Nanchang, Jiangxi 330006, China.

  • ↵3 Present address: Nanfang Hospital, Southern Medical University, Guangzhou 510000, China.

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.

Footnotes

  • ↵* This work was supported by American Diabetes Association Grant 1-16-IBS-146 and National Institutes of Health Grant R01DK094025 (to Z. Y. J.), a Boston University Clinical & Translational Science Institute (CTSI) Pilot Grant 1UL1TR001430 (to Q. L. Z.), a grant from the National Research Foundation Singapore and the Singapore Ministry of Health's National Medical Research Council under its Singapore Translational Research (STaR) Investigator Award (to D. G. T.), and visiting scholarships from the China Scholarship Council (to C. H., Y. S., and Z. L.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

  • ↵Graphic This article contains supplemental Experimental Procedures and supplemental Figs. 1–8.

  • Received September 18, 2016.
  • Revision received January 30, 2017.
View this article with LENS
Table of Contents

This Article

  1. First Published on February 15, 2017 doi: 10.1074/jbc.C116.758748 The Journal of Biological Chemistry 292, 4770-4776.
  1. » Abstract(Free)
  2. Full Text
  3. PDF
  4. PDF including Supp Data
  5. Supplemental Data
  6. All Versions of this Article:
    1. C116.758748v1
    2. 292/12/4770 (most recent)

Article Usage Stats

  1. Article Usage Statistics

Submit your work to JBC.

You'll be in good company.