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

Jun-Yuan Huang,Qiong Lin Zhou,Chun-Hong Huang,Ye Song,Andria G Sharma,Zhangping Liao,Kavin Zhu,Miles W Massidda,Ryan R Jamieson,Jun-Yuan Zhang,Daniel G Tenen,Zhen Y Jiang

doi:10.1074/jbc.c116.758748

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.

Highlights

Obesity is a major contributing factor to the development of insulin resistance, type II diabetes, and cardiovascular diseases
Our group and others have shown that short-term consumption of a high-fat diet (HFD)5 is sufficient to increase neutrophil infiltration into white adipose tissue, and mice that lack neutrophil elastase (NE) are resistant to HFD-induced leukocyte infiltration in adipose tissues and subsequent insulin resistance (8 –10)
Further analyses of the subset populations of KSL-HSPCs revealed that short-term HFD feeding rapidly increased multipotent progenitors (MPPs), whereas no significant change was observed with long-term and short-term hematopoietic stem cells (LT-HSCs and STHSCs, Fig. 1D)

Summary

Introduction

Obesity is a major contributing factor to the development of insulin resistance, type II diabetes, and cardiovascular diseases. Myelopoiesis Is Rapidly Increased by Short-term HFD Feeding—To determine whether HFD-induced leukocyte infiltration in adipose tissues is due to an increase in neutrophil production, we fed WT C57BL/6J mice with a normal chow diet

Results

Conclusion