Journal
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
Volume 35, Issue 6, Pages 1423-1433Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.114.304846
Keywords
chemokines; endothelial cells; macrophages; mucocutaneous lymph node syndrome; vasculitis
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Funding
- Health and Labour Sciences Research Grants from the Ministry of Health, Labour and Welfare, Japan
- Grants-in-Aid for Scientific Research [26110006, 26293089, 25253067, 26670447] Funding Source: KAKEN
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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.
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