Inositol-Triphosphate 3-Kinase C Mediates Inflammasome Activation and Treatment Response in Kawasaki Disease.
Kawasaki disease (KD) is a multisystem vasculitis that predominantly targets the coronary arteries in children. Phenotypic similarities between KD and recurrent fever syndromes point to the potential role of inflammasome activation in KD. Mutations in NLRP3 are associated with recurrent fever/autoinflammatory syndromes. We show that the KD-associated genetic polymorphism in inositol-triphosphate 3-kinase C (ITPKC) (rs28493229) has important functional consequences, governing ITPKC protein levels and thereby intracellular calcium, which in turn regulates NLRP3 expression and production of IL-1β and IL-18. Analysis of transcript abundance, protein levels, and cellular response profiles from matched, serial biospecimens from a cohort of genotyped KD subjects points to the critical role of ITPKC in mediating NLRP3 inflammasome activation. Treatment failure in those with the high-risk ITPKC genotype was associated with the highest basal and stimulated intracellular calcium levels and with increased cellular production of IL-1β and IL-18 and higher circulating levels of both cytokines. Mechanistic studies using Itpkc-deficient mice in a disease model support the genomic, cellular, and clinical findings in affected children. Our findings provide the mechanism behind the observed efficacy of rescue therapy with IL-1 blockade in recalcitrant KD, and we identify that regulation of calcium mobilization is fundamental to the underlying immunobiology in KD.
Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.|Cell Biology Research Program, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
Martin Prince
0000-0003-3447-1284
MP
Alphonse
Cell Biology Research Program, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
Trang T
0000-0003-2489-6123
TT
Duong
Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093.
Chisato
0000-0002-3149-2699
C
Shumitzu
Genome Institute of Singapore, Singapore 138672, Singapore.
Truong Long
TL
Hoang
Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
Brian W
BW
McCrindle
Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093.
Alessandra
A
Franco
Laboratory of Functional Genetics, GIGA-Research Center, University of Liege, 4000 Liege, Belgium; and.
Stéphane
0000-0002-5579-3840
S
Schurmans
Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
Dana J
DJ
Philpott
Genome Institute of Singapore, Singapore 138672, Singapore.
Martin L
0000-0001-8587-1849
ML
Hibberd
Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093.
Jane
J
Burns
Department of Pediatrics, Sanquin Blood Bank, 1066 Amsterdam, the Netherlands.
Taco W
TW
Kuijpers
Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada; rae.yeung@sickkids.ca.|Cell Biology Research Program, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.|Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
Rae S M
RS
Yeung
D000818:Animals; D002675:Child, Preschool; D015331:Cohort Studies; D003331:Coronary Vessels / Q000378:metabolism / Q000473:pathology*; D005838:Genotype; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism; D020382:Interleukin-18 / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009080:Mucocutaneous Lymph Node Syndrome / Q000235:genetics* / Q000276:immunology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D016896:Treatment Outcome
D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D017853:Phosphotransferases (Alcohol Group Acceptor); C051038:Inositol 1,4,5-trisphosphate 3-kinase