Macrophage Exosomes Resolve Atherosclerosis by Regulating Hematopoiesis and Inflammation via MicroRNA Cargo

Cell Rep. 2020 Jul 14;32(2):107881. doi: 10.1016/j.celrep.2020.107881.

Abstract

Developing strategies that promote the resolution of vascular inflammation and atherosclerosis remains a major therapeutic challenge. Here, we show that exosomes produced by naive bone marrow-derived macrophages (BMDM-exo) contain anti-inflammatory microRNA-99a/146b/378a that are further increased in exosomes produced by BMDM polarized with IL-4 (BMDM-IL-4-exo). These exosomal microRNAs suppress inflammation by targeting NF-κB and TNF-α signaling and foster M2 polarization in recipient macrophages. Repeated infusions of BMDM-IL-4-exo into Apoe-/- mice fed a Western diet reduce excessive hematopoiesis in the bone marrow and thereby the number of myeloid cells in the circulation and macrophages in aortic root lesions. This also leads to a reduction in necrotic lesion areas that collectively stabilize atheroma. Thus, BMDM-IL-4-exo may represent a useful therapeutic approach for atherosclerosis and other inflammatory disorders by targeting NF-κB and TNF-α via microRNA cargo delivery.

Keywords: atherosclerosis; exosome; extracellular vesicle; hematopoiesis; inflammation; macrophage; microRNA; monocyte.

Publication types

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

MeSH terms

  • Animals
  • Apolipoproteins E / deficiency
  • Apolipoproteins E / metabolism
  • Atherosclerosis / genetics*
  • Atherosclerosis / pathology*
  • Cell Polarity
  • Exosomes / metabolism*
  • Exosomes / ultrastructure
  • Gene Editing
  • Hematopoiesis / genetics*
  • Humans
  • Inflammation / genetics*
  • Inflammation / pathology*
  • Interleukin-4 / metabolism
  • Macrophages / metabolism*
  • Macrophages / ultrastructure
  • Mice, Inbred C57BL
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Myeloid Cells / metabolism
  • NF-kappa B / metabolism
  • Signal Transduction
  • Tissue Distribution
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Apolipoproteins E
  • MicroRNAs
  • NF-kappa B
  • Tumor Necrosis Factor-alpha
  • Interleukin-4