Identification of Pathogenic Cardiac CD11c+ Macrophages in Nod1-Mediated Acute Coronary Arteritis

Arterioscler Thromb Vasc Biol. 2015 Jun;35(6):1423-33. doi: 10.1161/ATVBAHA.114.304846. Epub 2015 Apr 2.


Objective: Nod1 is an intracellular pattern recognition receptor for bacterial peptidoglycan fragments. We previously reported that a synthetic Nod1 ligand, FK565, induced acute coronary arteritis in mice similar to that of Kawasaki disease. However, the molecular mechanisms underlying this characteristic inflammation have remained elusive.

Approach and results: We found that CD11c(+)MHC class II(+) cells accumulated in the heart of FK565-treated mice before arteritis development. Morphological features and gene expression signatures of the cardiac CD11c(+)MHC class II(+) cells suggested that this population is closely related to macrophages, and thus, we designated them cardiac CD11c(+) macrophages. Nod1 in nonhematopoietic cells, rather than hematopoietic cells, was required for the increase of cardiac CD11c(+) macrophages and arteritis development. Among nonhematopoietic cells, cardiac endothelial cells produced a large amount of chemokines in response to FK565. Endothelial cell-specific blockade of Nod1 signaling suppressed FK565-induced expression of these chemokines, accumulation of cardiac CD11c(+) macrophages, and subsequent coronary arteritis development. We also found that CCR2(+)Ly6C(hi) inflammatory monocytes in peripheral blood supplied precursors of cardiac CD11c(+) macrophages. CCR2-deficient mice or pertussis toxin-treated mice exhibited decreased numbers of cardiac CD11c(+) macrophages and reduced arteritis.

Conclusions: These results suggest that Ly6C(hi) monocytes are recruited to FK565-activated endothelial cells to generate cardiac CD11c(+) macrophages, which play a pivotal role in the pathogenesis of acute coronary arteritis.

Keywords: chemokines; endothelial cells; macrophages; mucocutaneous lymph node syndrome; vasculitis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Ly
  • Arteritis / chemically induced
  • Arteritis / metabolism*
  • CD11c Antigen
  • Chemokines / metabolism
  • Coronary Artery Disease / chemically induced
  • Coronary Artery Disease / metabolism*
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism
  • Macrophages / drug effects
  • Macrophages / metabolism*
  • Mice
  • Monocytes / metabolism
  • NF-kappa B / antagonists & inhibitors
  • Nod1 Signaling Adaptor Protein / metabolism*
  • Oligopeptides / pharmacology
  • Receptors, CCR2 / metabolism
  • Receptors, CCR5 / metabolism
  • Receptors, G-Protein-Coupled / antagonists & inhibitors


  • Antigens, Ly
  • CCR5 protein, mouse
  • CD11c Antigen
  • Ccr2 protein, mouse
  • Chemokines
  • Ly-6C antigen, mouse
  • NF-kappa B
  • Nod1 Signaling Adaptor Protein
  • Oligopeptides
  • Receptors, CCR2
  • Receptors, CCR5
  • Receptors, G-Protein-Coupled
  • heptanoyl-gamma-D-glutamyl-L-meso-diaminopimelyl-D-alanine