title: 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.
  
  
  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.affiliation: From the Division of Molecular Immunology, Research Center for Infectious Diseases, Medical Institute of Bioregulation (Y.M., S.Y.), Department of Pediatrics, Graduate School of Medical Sciences (Y.M., S.K., H.N., T.H.), Kyushu University, Fukuoka, Japan; Laboratory of Immune Regulation, School of Life Science, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan (K.A.); Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan (Y.H., H.K.); Laboratory for Cell Signaling, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan (T.S.); Laboratory for Cell Signaling, World Premier International Research Center, Immunology Frontier Research Center, Osaka University, Osaka, Japan (T.S.); Department of Biomolecular Sciences, Faculty of Medicine, Saga University, Saga, Japan (H.H.); and Division of Molecular Immunology, Project for Host Response, Medical Mycology Research Center, Chiba University, Chiba, Japan (S.Y.).
authors.forename: Yoshitomo
authors.initials: Y
authors.lastname: Motomura
authors.affiliation: From the Division of Molecular Immunology, Research Center for Infectious Diseases, Medical Institute of Bioregulation (Y.M., S.Y.), Department of Pediatrics, Graduate School of Medical Sciences (Y.M., S.K., H.N., T.H.), Kyushu University, Fukuoka, Japan; Laboratory of Immune Regulation, School of Life Science, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan (K.A.); Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan (Y.H., H.K.); Laboratory for Cell Signaling, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan (T.S.); Laboratory for Cell Signaling, World Premier International Research Center, Immunology Frontier Research Center, Osaka University, Osaka, Japan (T.S.); Department of Biomolecular Sciences, Faculty of Medicine, Saga University, Saga, Japan (H.H.); and Division of Molecular Immunology, Project for Host Response, Medical Mycology Research Center, Chiba University, Chiba, Japan (S.Y.).
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Kanno
authors.affiliation: From the Division of Molecular Immunology, Research Center for Infectious Diseases, Medical Institute of Bioregulation (Y.M., S.Y.), Department of Pediatrics, Graduate School of Medical Sciences (Y.M., S.K., H.N., T.H.), Kyushu University, Fukuoka, Japan; Laboratory of Immune Regulation, School of Life Science, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan (K.A.); Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan (Y.H., H.K.); Laboratory for Cell Signaling, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan (T.S.); Laboratory for Cell Signaling, World Premier International Research Center, Immunology Frontier Research Center, Osaka University, Osaka, Japan (T.S.); Department of Biomolecular Sciences, Faculty of Medicine, Saga University, Saga, Japan (H.H.); and Division of Molecular Immunology, Project for Host Response, Medical Mycology Research Center, Chiba University, Chiba, Japan (S.Y.).
authors.forename: Kenichi
authors.initials: K
authors.lastname: Asano
authors.affiliation: From the Division of Molecular Immunology, Research Center for Infectious Diseases, Medical Institute of Bioregulation (Y.M., S.Y.), Department of Pediatrics, Graduate School of Medical Sciences (Y.M., S.K., H.N., T.H.), Kyushu University, Fukuoka, Japan; Laboratory of Immune Regulation, School of Life Science, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan (K.A.); Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan (Y.H., H.K.); Laboratory for Cell Signaling, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan (T.S.); Laboratory for Cell Signaling, World Premier International Research Center, Immunology Frontier Research Center, Osaka University, Osaka, Japan (T.S.); Department of Biomolecular Sciences, Faculty of Medicine, Saga University, Saga, Japan (H.H.); and Division of Molecular Immunology, Project for Host Response, Medical Mycology Research Center, Chiba University, Chiba, Japan (S.Y.).
authors.forename: Masato
authors.initials: M
authors.lastname: Tanaka
authors.affiliation: From the Division of Molecular Immunology, Research Center for Infectious Diseases, Medical Institute of Bioregulation (Y.M., S.Y.), Department of Pediatrics, Graduate School of Medical Sciences (Y.M., S.K., H.N., T.H.), Kyushu University, Fukuoka, Japan; Laboratory of Immune Regulation, School of Life Science, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan (K.A.); Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan (Y.H., H.K.); Laboratory for Cell Signaling, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan (T.S.); Laboratory for Cell Signaling, World Premier International Research Center, Immunology Frontier Research Center, Osaka University, Osaka, Japan (T.S.); Department of Biomolecular Sciences, Faculty of Medicine, Saga University, Saga, Japan (H.H.); and Division of Molecular Immunology, Project for Host Response, Medical Mycology Research Center, Chiba University, Chiba, Japan (S.Y.).
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Hasegawa
authors.affiliation: From the Division of Molecular Immunology, Research Center for Infectious Diseases, Medical Institute of Bioregulation (Y.M., S.Y.), Department of Pediatrics, Graduate School of Medical Sciences (Y.M., S.K., H.N., T.H.), Kyushu University, Fukuoka, Japan; Laboratory of Immune Regulation, School of Life Science, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan (K.A.); Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan (Y.H., H.K.); Laboratory for Cell Signaling, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan (T.S.); Laboratory for Cell Signaling, World Premier International Research Center, Immunology Frontier Research Center, Osaka University, Osaka, Japan (T.S.); Department of Biomolecular Sciences, Faculty of Medicine, Saga University, Saga, Japan (H.H.); and Division of Molecular Immunology, Project for Host Response, Medical Mycology Research Center, Chiba University, Chiba, Japan (S.Y.).
authors.forename: Hideki
authors.initials: H
authors.lastname: Katagiri
authors.affiliation: From the Division of Molecular Immunology, Research Center for Infectious Diseases, Medical Institute of Bioregulation (Y.M., S.Y.), Department of Pediatrics, Graduate School of Medical Sciences (Y.M., S.K., H.N., T.H.), Kyushu University, Fukuoka, Japan; Laboratory of Immune Regulation, School of Life Science, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan (K.A.); Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan (Y.H., H.K.); Laboratory for Cell Signaling, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan (T.S.); Laboratory for Cell Signaling, World Premier International Research Center, Immunology Frontier Research Center, Osaka University, Osaka, Japan (T.S.); Department of Biomolecular Sciences, Faculty of Medicine, Saga University, Saga, Japan (H.H.); and Division of Molecular Immunology, Project for Host Response, Medical Mycology Research Center, Chiba University, Chiba, Japan (S.Y.).
authors.forename: Takashi
authors.initials: T
authors.lastname: Saito
authors.affiliation: From the Division of Molecular Immunology, Research Center for Infectious Diseases, Medical Institute of Bioregulation (Y.M., S.Y.), Department of Pediatrics, Graduate School of Medical Sciences (Y.M., S.K., H.N., T.H.), Kyushu University, Fukuoka, Japan; Laboratory of Immune Regulation, School of Life Science, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan (K.A.); Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan (Y.H., H.K.); Laboratory for Cell Signaling, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan (T.S.); Laboratory for Cell Signaling, World Premier International Research Center, Immunology Frontier Research Center, Osaka University, Osaka, Japan (T.S.); Department of Biomolecular Sciences, Faculty of Medicine, Saga University, Saga, Japan (H.H.); and Division of Molecular Immunology, Project for Host Response, Medical Mycology Research Center, Chiba University, Chiba, Japan (S.Y.).
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Hara
authors.affiliation: From the Division of Molecular Immunology, Research Center for Infectious Diseases, Medical Institute of Bioregulation (Y.M., S.Y.), Department of Pediatrics, Graduate School of Medical Sciences (Y.M., S.K., H.N., T.H.), Kyushu University, Fukuoka, Japan; Laboratory of Immune Regulation, School of Life Science, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan (K.A.); Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan (Y.H., H.K.); Laboratory for Cell Signaling, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan (T.S.); Laboratory for Cell Signaling, World Premier International Research Center, Immunology Frontier Research Center, Osaka University, Osaka, Japan (T.S.); Department of Biomolecular Sciences, Faculty of Medicine, Saga University, Saga, Japan (H.H.); and Division of Molecular Immunology, Project for Host Response, Medical Mycology Research Center, Chiba University, Chiba, Japan (S.Y.).
authors.forename: Hisanori
authors.initials: H
authors.lastname: Nishio
authors.affiliation: From the Division of Molecular Immunology, Research Center for Infectious Diseases, Medical Institute of Bioregulation (Y.M., S.Y.), Department of Pediatrics, Graduate School of Medical Sciences (Y.M., S.K., H.N., T.H.), Kyushu University, Fukuoka, Japan; Laboratory of Immune Regulation, School of Life Science, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan (K.A.); Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan (Y.H., H.K.); Laboratory for Cell Signaling, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan (T.S.); Laboratory for Cell Signaling, World Premier International Research Center, Immunology Frontier Research Center, Osaka University, Osaka, Japan (T.S.); Department of Biomolecular Sciences, Faculty of Medicine, Saga University, Saga, Japan (H.H.); and Division of Molecular Immunology, Project for Host Response, Medical Mycology Research Center, Chiba University, Chiba, Japan (S.Y.).
authors.forename: Toshiro
authors.initials: T
authors.lastname: Hara
authors.affiliation: From the Division of Molecular Immunology, Research Center for Infectious Diseases, Medical Institute of Bioregulation (Y.M., S.Y.), Department of Pediatrics, Graduate School of Medical Sciences (Y.M., S.K., H.N., T.H.), Kyushu University, Fukuoka, Japan; Laboratory of Immune Regulation, School of Life Science, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan (K.A.); Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan (Y.H., H.K.); Laboratory for Cell Signaling, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan (T.S.); Laboratory for Cell Signaling, World Premier International Research Center, Immunology Frontier Research Center, Osaka University, Osaka, Japan (T.S.); Department of Biomolecular Sciences, Faculty of Medicine, Saga University, Saga, Japan (H.H.); and Division of Molecular Immunology, Project for Host Response, Medical Mycology Research Center, Chiba University, Chiba, Japan (S.Y.). yamasaki@bioreg.kyushu-u.ac.jp.
authors.forename: Sho
authors.initials: S
authors.lastname: Yamasaki
mesh_terms: D000818:Animals; D000950:Antigens, Ly; D001167:Arteritis / Q000139:chemically induced / Q000378:metabolism*; D039521:CD11c Antigen; D018925:Chemokines / Q000378:metabolism; D003324:Coronary Artery Disease / Q000139:chemically induced / Q000378:metabolism*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D009000:Monocytes / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D053474:Nod1 Signaling Adaptor Protein / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D054390:Receptors, CCR2 / Q000378:metabolism; D019713:Receptors, CCR5 / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors
chemical_list: D000950:Antigens, Ly; C000592874:CCR5 protein, mouse; D039521:CD11c Antigen; C515335:Ccr2 protein, mouse; D018925:Chemokines; C494192:Ly-6C antigen, mouse; D016328:NF-kappa B; D053474:Nod1 Signaling Adaptor Protein; D009842:Oligopeptides; D054390:Receptors, CCR2; D019713:Receptors, CCR5; D043562:Receptors, G-Protein-Coupled; C039537:heptanoyl-gamma-D-glutamyl-L-meso-diaminopimelyl-D-alanine
keywords: chemokines; endothelial cells; macrophages; mucocutaneous lymph node syndrome; vasculitis