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

Abstract

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.

• Authors: Yoshitomo Motomura, Shunsuke Kanno, Kenichi Asano, Masato Tanaka, Yutaka Hasegawa, Hideki Katagiri, Takashi Saito, Hiromitsu Hara, Hisanori Nishio, Toshiro Hara, Sho Yamasaki
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 35 Issue 6 Pg. 1423-33 (Jun 2015) ISSN: 1524-4636 [Electronic] United States
• PMID: 25838430 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 American Heart Association, Inc.

Chemical References

• 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

Topics

• Animals
• Antigens, Ly
• Arteritis (chemically induced, metabolism)
• CD11c Antigen
• Chemokines (metabolism)
• Coronary Artery Disease (chemically induced, metabolism)
• Endothelial Cells (drug effects, metabolism)
• Macrophages (drug effects, 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)