Editors' ChoiceKawasaki Disease

The inflammasome keeps on breaking your heart

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Science Translational Medicine  19 Oct 2016:
Vol. 8, Issue 361, pp. 361ec168
DOI: 10.1126/scitranslmed.aai9164

Kawasaki disease (KD) is a multisystem vasculitis most commonly occurring in children. Although the cause is unknown, the clinical syndrome is well described: A young child presents with many days of high-grade fever in association with rash, cracked lips, strawberry tongue, cervical adenopathy, and red eyes, palms, and soles of the feet. In the absence of recognition and treatment, coronary artery aneurysms will develop in about one-quarter of these children. Treatment with IVIg is effective, but still about 20% of patients recrudesce after therapy for unknown reasons. A recent manuscript by Alphonse and colleagues sheds light on the immunologic challenges in this disease.

Genomic approaches have previously implicated inositol-triphosphate 3-kinase C (ITPKC) as a determinant of both disease risk and outcome. Because the inositol triphosphate system regulates calcium stores, the authors hypothesized that this signaling axis would intersect with inflammasome activation to increase interleukin-1β (IL-1β) activation, which promotes KD. The authors established a mechanistic link using an ITPKC-deficient mouse in which ITPKC-deficient macrophages had increased stimulated calcium flux, more NLRP3 inflammasome activation, and increased IL-1β production in a model of KD in which coronary arteritis is induced by intraperitoneal injection of Lactobacillus casei wall extract. They extended these findings to analysis of children with the high-risk ITPKC polymorphism. Patients with the polymorphism had decreased ITPKC protein expression, increased calcium flux, and increased expression of NLRP3. Last, the clinical response to IVIg was reduced in children with the highest-risk genotype; only 40% of these children responded to therapy compared with nearly 80% of lower-risk individuals.

The authors identify a regulatory network in which ITPKC controls calcium release by shuttling inositol triphosphate (IP3) to inositol tetraphosphate (IP4). In the absence of ITPKC, IP3 concentrations increase, resulting in unrestrained calcium mobilization and inflammasome activation. This response makes these children refractory to IVIg immune therapy, the most common treatment for KD, but also may explain why they can be rescued with IL-1 targeting intervention. Future approaches to identify children who are most at risk of adverse outcomes and to intervene in a pathway-specific fashion are likely to mend more hearts before they are broken.

M. P. Alphonse et al., Inositol-triphosphate 3-kinase C mediates inflammasome activation and treatment response in Kawasaki disease. J. Immunol. 10.4049/jimmunol.1600388 (2016). [Abstract]

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