RRC ID 52273
Author Murata K, Motomura Y, Tanaka T, Kanno S, Yano T, Onimaru M, Shimoyama A, Nishio H, Sakai Y, Oh-Hora M, Hara H, Fukase K, Takada H, Masuda S, Ohga S, Yamasaki S, Hara T.
Title Calcineurin inhibitors exacerbate coronary arteritis via the MyD88 signalling pathway in a murine model of Kawasaki disease.
Journal Clin Exp Immunol
Abstract Calcineurin inhibitors (CNIs) have been used off-label for the treatment of refractory Kawasaki disease (KD). However, it remains unknown whether CNIs show protective effects against the development of coronary artery lesions in KD patients. To investigate the effects of CNIs on coronary arteries and the mechanisms of their actions on coronary arteritis in a mouse model of KD, we performed experiments with FK565, a ligand of nucleotide-binding oligomerization domain-containing protein 1 (NOD1) in wild-type, severe combined immunodeficiency (SCID), caspase-associated recruitment domain 9 (CARD9)-/- and myeloid differentiation primary response gene 88 (MyD88)-/- mice. We also performed in-vitro studies with vascular and monocytic cells and vascular tissues. A histopathological analysis showed that both cyclosporin A and tacrolimus exacerbated the NOD1-mediated coronary arteritis in a dose-dependent manner. Cyclosporin A induced the exacerbation of coronary arteritis in mice only in high doses, while tacrolimus exacerbated it within the therapeutic range in humans. Similar effects were obtained in SCID and CARD9-/- mice but not in MyD88-/- mice. CNIs enhanced the expression of adhesion molecules by endothelial cells and the cytokine secretion by monocytic cells in our KD model. These data indicated that both vascular and monocytic cells were involved in the exacerbation of coronary arteritis. Activation of MyD88-dependent inflammatory signals in both vascular cells and macrophages appears to contribute to their adverse effects. Particular attention should be paid to the development of coronary artery lesions when using CNIs to treat refractory KD.
Volume 190(1)
Pages 54-67
Published 2017-10
DOI 10.1111/cei.13002
PMID 28640392
PMC PMC5588765
MeSH Animals Arteritis / drug therapy* CARD Signaling Adaptor Proteins / genetics Calcineurin Inhibitors / therapeutic use* Coronary Vessels / pathology Cytokines / metabolism Disease Models, Animal Endothelium, Vascular / drug effects* Endothelium, Vascular / immunology Humans Inflammation Mediators / metabolism Macrophages / drug effects* Macrophages / immunology Mice Mice, Inbred C57BL Mice, Knockout Mice, SCID Mucocutaneous Lymph Node Syndrome / drug therapy* Myeloid Differentiation Factor 88 / genetics Myeloid Differentiation Factor 88 / metabolism* Oligopeptides / therapeutic use* RAW 264.7 Cells Signal Transduction
IF 3.711
Times Cited 4
Human and Animal Cells RAW 264(RCB0535)