Abstract
ObjectiveKawasaki disease (KD) is the most common cause of acquired pediatric heart disease in the developed world. 10% of KD patients are resistant to front-line therapy, and no interventions exist to address secondary complications such as myocardial fibrosis. We sought to identify proteins and pathways associated with disease and anti-IL-1 treatment in a mouse model of KD.MethodsVasculitis was induced via Lactobacillus casei cell wall extract (LCWE) injection in 5-week-old male mice. Groups of mice were injected with LCWE alone, LCWE and IL-1 receptor antagonist anakinra, or saline for controls. Upper heart tissue was assessed by quantitative mass spectrometry analysis. Expression and activation of STAT3 was assessed by immunohistochemistry, immunofluorescence and Western blot, and IL-6 expression by RNA-seq and ELISA. A STAT3 small molecular inhibitor and anti-IL-6R antibody were used to evaluate the role of STAT3 and IL-6 in disease development.ResultsSTAT3 was highly expressed and phosphorylated in cardiac tissue of LCWE-injected mice, and reduced following anakinra treatment. Il6 and Stat3 gene expression was enhanced in abdominal aorta of LCWE-injected mice and reduced with Anakinra treatment. IL-6 serum levels were enhanced in LCWE-injected mice and normalized by anakinra. However, neither inhibition of STAT3 nor blockade of IL-6 altered disease development.ConclusionProteomic analysis of cardiac tissues demonstrates differential protein expression between KD-like, control and anakinra treated cardiac tissue. STAT3 and IL-6 were highly upregulated with LCWE and normalized by anakinra treatment. However, both STAT3 and IL-6 were dispensable for disease development indicating they may be bystanders of inflammation.
Highlights
Kawasaki disease (KD) is a relatively common febrile disease and vasculitis of childhood (10-20/100,000 incidence in North America) of unknown etiology, and typically presents as a febrile illness with features including rash, mucositis and conjunctivitis in children from ages 6 months to 5 years [1]
STAT3 and IL-6 were highly upregulated with Lactobacillus casei cell wall extract (LCWE) and normalized by anakinra treatment
We performed proteomics analysis to evaluate the changes in cardiac tissue protein expression during LCWE-induced KD vasculitis and the response to anakinra treatment
Summary
Kawasaki disease (KD) is a relatively common febrile disease and vasculitis of childhood (10-20/100,000 incidence in North America) of unknown etiology, and typically presents as a febrile illness with features including rash, mucositis and conjunctivitis in children from ages 6 months to 5 years [1]. While the acute process is self-limited, many patients with KD subsequently develop inflammatory vasculitic lesions of the coronary vasculature, resulting in coronary artery aneurysms (CAA). An emerging concern in the KD field is the recognition some patients develop late-onset myocardial fibrosis, which can lead to heart failure and death [1, 2]. Current management of KD is focused on preventing coronary artery aneurysms, and is anchored by the use of intravenous immunoglobulin (IVIG). Beyond surveillance for sequelae, there is no current management or therapy for myocardial fibrosis in KD [5]. Despite current treatment and practices, KD remains the most common cause of acquired heart disease in children in the US and developed world [1]. Approximately 10% of all KD patients are resistant to initial IVIG therapy, and require adjunctive treatment [6]
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