Inositol-Triphosphate 3-Kinase C Mediates Inflammasome Activation and Treatment Response in Kawasaki Disease.

Abstract

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.

• Authors: Martin Prince Alphonse, Trang T Duong, Chisato Shumitzu, Truong Long Hoang, Brian W McCrindle, Alessandra Franco, Stéphane Schurmans, Dana J Philpott, Martin L Hibberd, Jane Burns, Taco W Kuijpers, Rae S M Yeung
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 197 Issue 9 Pg. 3481-3489 (11 01 2016) ISSN: 1550-6606 [Electronic] United States
• PMID: 27694492 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 by The American Association of Immunologists, Inc.

Chemical References

• Inflammasomes
• Interleukin-18
• Interleukin-1beta
• NLR Family, Pyrin Domain-Containing 3 Protein
• Phosphotransferases (Alcohol Group Acceptor)
• Inositol 1,4,5-trisphosphate 3-kinase

Topics

• Animals
• Child, Preschool
• Cohort Studies
• Coronary Vessels (metabolism, pathology)
• Genotype
• Humans
• Inflammasomes (metabolism)
• Interleukin-18 (genetics, metabolism)
• Interleukin-1beta (genetics, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mucocutaneous Lymph Node Syndrome (genetics, immunology)
• NLR Family, Pyrin Domain-Containing 3 Protein (metabolism)
• Phosphotransferases (Alcohol Group Acceptor) (genetics)
• Polymorphism, Single Nucleotide
• Risk
• Treatment Outcome