Platelet-Monocyte Aggregate Instigates Inflammation and Vasculopathy in Kawasaki Disease
Yuan Zhang1, Cuiping Jia1, Manli Guo1
1Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China.
Insights
Kawasaki disease involves platelet-monocyte interactions driving inflammation. Targeting these interactions, like P-selectin and TGF-β1, may prevent vasculopathy in children.
Area of Science:
- Immunology
- Hematology
- Pediatric Cardiology
Background:
- Kawasaki disease (KD) is a critical illness in children, characterized by systemic vasculitis and potential coronary artery aneurysms.
- Platelet hyperreactivity and immune dysregulation are hallmarks of KD, but the precise role of platelets in KD pathogenesis is not fully understood.
- Understanding platelet-monocyte interactions is crucial for elucidating KD-induced inflammation and vasculopathy.
Purpose of the Study:
- To investigate the mechanism of platelet-monocyte aggregation in Kawasaki disease.
- To identify key molecular interactions and cytokine mediators involved in KD pathogenesis.
- To explore potential therapeutic targets for preventing KD-associated vasculopathy.
Main Methods:
- Analysis of platelet-monocyte aggregates (MPAs) in KD patients.
- Investigation of P-selectin (CD62p)/PSGL-1 and GPIbα/CD11b interactions.
- Assessment of transforming growth factor-β1 (TGF-β1) signaling in monocytes.
- Evaluation of monocyte phenotypic conversion (CD14+CD16-) to pro-inflammatory (CD14+CD16+) states.
- Murine models deficient in platelet TGF-β1 were used to assess in vivo effects.
Main Results:
- A positive feedback loop between KD platelets and monocytes was identified, mediated by specific adhesion molecules.
- KD MPAs involve sequential interactions of CD62p/PSGL-1 and GPIbα/CD11b.
- Platelet-derived TGF-β1 induces nuclear factor kappaB localization in monocytes, promoting their pro-inflammatory phenotype.
- Inhibition of this feedback loop components prevented KD-induced inflammation and vasculopathy.
- Mice lacking platelet TGF-β1 exhibited reduced MPAs, fewer pro-inflammatory monocytes, and diminished vasculopathy.
Conclusions:
- Platelet-monocyte interactions form a critical cytokine-mediated positive feedback loop in Kawasaki disease.
- Specific platelet proteins (CD62p, GPIbα) and monocyte receptors (PSGL-1, CD11b) are key mediators of these interactions.
- Platelet TGF-β1 plays a significant role in driving monocyte activation and KD vasculopathy.
- Targeting platelet-monocyte interactive proteins and TGF-β1 offers promising therapeutic strategies for KD vasculopathy.
Abstract:
Kawasaki disease (KD) is a severe acute febrile illness and systemic vasculitis that causes coronary artery aneurysms in young children. Platelet hyperreactivity and an aberrant immune response are key indicators of KD; however, the mechanism by which hyperactive platelets contribute to inflammation and vasculopathy in KD remains unclear. A cytokine-mediated positive feedback loop between KD platelets and monocytes is identified. KD platelet-monocyte aggregates (MPAs) are mediated by an initial interaction of P-selectin (cluster of differentiation 62P, CD62p) and its glycoprotein ligand 1 (PSGL-1). This is followed by a coordinated interaction of platelet glycoprotein (GP)Ibα with monocyte CD11b. Monocyte-activated platelets initiate transforming growth factor (TGF)β1 release, which results in nuclear localization of nuclear factor kappaB in monocytes, therefore, driving the phenotypic conversion of classical monocytes (CD14+CD16-) into proinflammatory monocytes (CD14+CD16+). The platelet-activated monocytes release interleukin-1 and tissue necrotic factor-α, which promote further platelet activation. KD-induced inflammation and vasculopathy are prevented by inhibiting the components of this positive feedback loop. Notably, mice deficient in platelet TGFβ1 show less MPA and CD14+CD16+ monocytes, along with reduced inflammation and vasculopathy. These findings reveal that platelet-monocyte interactive proteins (CD62p/PSGL-1 and (GP)Ibα/CD11b) and cytokine mediators (platelet TGFβ1) are potential biomarkers and therapeutic targets for KD vasculopathy.
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