GM-CSF primes cardiac inflammation in a mouse model of Kawasaki disease.
Kawasaki disease (KD) is the leading cause of pediatric heart disease in developed countries. KD patients develop cardiac inflammation, characterized by an early infiltrate of neutrophils and monocytes that precipitates coronary arteritis. Although the early inflammatory processes are linked to cardiac pathology, the factors that regulate cardiac inflammation and immune cell recruitment to the heart remain obscure. In this study, using a mouse model of KD (induced by a cell wall Candida albicans water-soluble fraction [CAWS]), we identify an essential role for granulocyte/macrophage colony-stimulating factor (GM-CSF) in orchestrating these events. GM-CSF is rapidly produced by cardiac fibroblasts after CAWS challenge, precipitating cardiac inflammation. Mechanistically, GM-CSF acts upon the local macrophage compartment, driving the expression of inflammatory cytokines and chemokines, whereas therapeutically, GM-CSF blockade markedly reduces cardiac disease. Our findings describe a novel role for GM-CSF as an essential initiating cytokine in cardiac inflammation and implicate GM-CSF as a potential target for therapeutic intervention in KD.
The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3052, Australia stock.a@wehi.edu.au wicks@wehi.edu.au.
Angus T
AT
Stock
The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3052, Australia.
Jacinta A
0000-0001-5502-8391
JA
Hansen
Department of Respiratory, Inflammation, and Autoimmunity Research, MedImmune Limited, Cambridge CB21 6GH, England, UK.
Matthew A
0000-0003-2945-0315
MA
Sleeman
CSL Limited Research Department, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, Victoria 3052, Australia.
Brent S
BS
McKenzie
The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3052, Australia Department of Medical Biology, University of Melbourne, Melbourne, Victoria 3052, Australia Rheumatology Unit, The Royal Melbourne Hospital, Parkville, Victoria 3050, Australia stock.a@wehi.edu.au wicks@wehi.edu.au.
Ian P
IP
Wicks
D000818:Animals; D002176:Candida albicans / Q000378:metabolism; D002451:Cell Compartmentation; D018925:Chemokines / Q000378:metabolism; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000172:deficiency / Q000378:metabolism*; D006410:Hematopoiesis; D007249:Inflammation / Q000150:complications / Q000235:genetics / Q000473:pathology*; D007700:Kinetics; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000473:pathology; D009080:Mucocutaneous Lymph Node Syndrome / Q000150:complications / Q000473:pathology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D009504:Neutrophils / Q000473:pathology; D009928:Organ Specificity; D011836:Radiation Tolerance; D015398:Signal Transduction; D014657:Vasculitis / Q000150:complications / Q000473:pathology
D018925:Chemokines; D016178:Granulocyte-Macrophage Colony-Stimulating Factor