The persistence of low-grade inflammatory monocytes contributes to aggravated atherosclerosis

Nat Commun. 2016 Nov 8;7:13436. doi: 10.1038/ncomms13436.

Abstract

Sustained low-grade inflammation mediated by non-resolving inflammatory monocytes has long been suspected in the pathogenesis of atherosclerosis; however, the molecular mechanisms responsible for the sustainment of non-resolving inflammatory monocytes during atherosclerosis are poorly understood. Here we observe that subclinical endotoxemia, often seen in humans with chronic inflammation, aggravates murine atherosclerosis through programming monocytes into a non-resolving inflammatory state with elevated Ly6C, CCR5, MCP-1 and reduced SR-B1. The sustainment of inflammatory monocytes is due to the disruption of homeostatic tolerance through the elevation of miR-24 and reduction of the key negative-feedback regulator IRAK-M. miR-24 reduces the levels of Smad4 required for the expression of IRAK-M and also downregulates key lipid-processing molecule SR-B1. IRAK-M deficiency in turn leads to elevated miR-24 levels, sustains disruption of monocyte homeostasis and aggravates atherosclerosis. Our data define an integrated feedback circuit in monocytes and its disruption may lead to non-resolving low-grade inflammation conducive to atherosclerosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Atherosclerosis / metabolism
  • Atherosclerosis / pathology*
  • Base Sequence
  • Cell Polarity
  • Disease Progression
  • Endotoxemia / metabolism
  • Endotoxemia / pathology*
  • Homeostasis
  • Inflammation / metabolism
  • Inflammation / pathology*
  • Interleukin-1 Receptor-Associated Kinases / deficiency
  • Interleukin-1 Receptor-Associated Kinases / metabolism
  • Lipopolysaccharides
  • Mice, Inbred C57BL
  • MicroRNAs / metabolism
  • Monocytes / metabolism
  • Monocytes / pathology*
  • Scavenger Receptors, Class B / metabolism
  • Smad4 Protein / metabolism

Substances

  • Lipopolysaccharides
  • MicroRNAs
  • Mirn24 microRNA, mouse
  • Scarb1 protein, mouse
  • Scavenger Receptors, Class B
  • Smad4 Protein
  • Interleukin-1 Receptor-Associated Kinases
  • Irak3 protein, mouse