Platelets exacerbate cardiovascular inflammation in a murine model of Kawasaki disease vasculitis
Begüm Kocatürk1,2, Youngho Lee1,2, Nobuyuki Nosaka1,2
1Department of Pediatrics, Division of Infectious Diseases and Immunology, Guerin Children's at Cedars-Sinai Medical Center, Los Angeles, California, USA.
Insights
Platelets worsen cardiovascular inflammation in Kawasaki disease (KD). Targeting platelet activation and monocyte-platelet aggregates may offer new therapeutic strategies for this childhood condition.
Area of Science:
- Immunology
- Cardiovascular Research
- Pediatric Disease
Background:
- Kawasaki disease (KD) is a primary cause of acquired heart disease in children.
- Elevated platelet counts and activation are linked to severe KD outcomes, including coronary artery aneurysms.
- The precise role of platelets in KD pathogenesis is not fully understood.
Purpose of the Study:
- To investigate the role of platelets in Kawasaki disease vasculitis pathogenesis.
- To explore the impact of platelet activation and monocyte-platelet aggregates (MPAs) on cardiovascular inflammation in a KD mouse model.
Main Methods:
- Analysis of whole blood transcriptomics data from KD patients.
- Utilized a Lactobacillus casei cell wall extract (LCWE) murine model of KD vasculitis.
- Assessed platelet counts, MPAs, soluble P-selectin, thrombopoietin, IL-6, and cardiovascular lesions.
- Investigated the effect of platelet depletion (Mpl-/- mice) and anti-CD42b antibody treatment.
Main Results:
- LCWE injection increased platelet counts, MPA formation, soluble P-selectin, thrombopoietin, and IL-6 levels in mice.
- Platelet counts positively correlated with the severity of cardiovascular inflammation.
- Platelet depletion or blockade significantly reduced LCWE-induced cardiovascular lesions.
- Platelets, via MPAs, appear to promote vascular inflammation and IL-1B production in the KD model.
Conclusions:
- Platelet activation exacerbates cardiovascular lesions in a murine model of Kawasaki disease vasculitis.
- Monocyte-platelet aggregates (MPAs) are implicated in amplifying IL-1B production, contributing to disease severity.
- Platelets and MPAs represent potential therapeutic targets for Kawasaki disease.
Abstract:
Kawasaki disease (KD) is the leading cause of acquired heart disease among children. Increased platelet counts and activation are observed during the course of KD, and elevated platelet counts are associated with higher risks of developing intravenous immunoglobulin resistance and coronary artery aneurysms. However, the role of platelets in KD pathogenesis remains unclear. Here, we analyzed transcriptomics data generated from the whole blood of patients with KD and discovered changes in the expression of platelet-related genes during acute KD. In the Lactobacillus casei cell wall extract (LCWE) murine model of KD vasculitis, LCWE injection increased platelet counts and the formation of monocyte-platelet aggregates (MPAs), upregulated the concentration of soluble P-selectin, and increased circulating thrombopoietin and interleukin 6 (IL-6). Furthermore, platelet counts correlated with the severity of cardiovascular inflammation. Genetic depletion of platelets (Mpl-/- mice) or treatment with an anti-CD42b antibody significantly reduced LCWE-induced cardiovascular lesions. Furthermore, in the mouse model, platelets promoted vascular inflammation via the formation of MPAs, which likely amplified IL-1B production. Altogether, our results indicate that platelet activation exacerbates the development of cardiovascular lesions in a murine model of KD vasculitis. These findings enhance our understanding of KD vasculitis pathogenesis and highlight MPAs, which are known to enhance IL-1B production, as a potential therapeutic target for this disorder.
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