MyD88-dependent interplay between myeloid and endothelial cells in the initiation and progression of obesity-associated inflammatory diseases

J Exp Med. 2014 May 5;211(5):887-907. doi: 10.1084/jem.20131314. Epub 2014 Apr 21.

Abstract

Low-grade systemic inflammation is often associated with metabolic syndrome, which plays a critical role in the development of the obesity-associated inflammatory diseases, including insulin resistance and atherosclerosis. Here, we investigate how Toll-like receptor-MyD88 signaling in myeloid and endothelial cells coordinately participates in the initiation and progression of high fat diet-induced systemic inflammation and metabolic inflammatory diseases. MyD88 deficiency in myeloid cells inhibits macrophage recruitment to adipose tissue and their switch to an M1-like phenotype. This is accompanied by substantially reduced diet-induced systemic inflammation, insulin resistance, and atherosclerosis. MyD88 deficiency in endothelial cells results in a moderate reduction in diet-induced adipose macrophage infiltration and M1 polarization, selective insulin sensitivity in adipose tissue, and amelioration of spontaneous atherosclerosis. Both in vivo and ex vivo studies suggest that MyD88-dependent GM-CSF production from the endothelial cells might play a critical role in the initiation of obesity-associated inflammation and development of atherosclerosis by priming the monocytes in the adipose and arterial tissues to differentiate into M1-like inflammatory macrophages. Collectively, these results implicate a critical MyD88-dependent interplay between myeloid and endothelial cells in the initiation and progression of obesity-associated inflammatory diseases.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Analysis of Variance
  • Animals
  • CD11b Antigen / metabolism
  • Endothelial Cells / metabolism*
  • Flow Cytometry
  • Immunohistochemistry
  • Inflammation / etiology
  • Inflammation / metabolism*
  • Inflammation / physiopathology*
  • Insulin / metabolism*
  • Mice
  • Myeloid Cells / metabolism*
  • Myeloid Differentiation Factor 88 / metabolism*
  • Obesity / complications*
  • Real-Time Polymerase Chain Reaction

Substances

  • CD11b Antigen
  • Insulin
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88