Thymic stromal lymphopoietin induces platelet mitophagy and promotes thrombosis in Kawasaki disease

Abstract

Kawasaki disease (KD) is an acute systemic vasculitis primarily affecting infants and children. Activated platelets predispose patients to coronary artery structural lesions that may lead to thrombotic cardiovascular events. To discover potential proteins underlying platelet activation in KD, we conducted a protein chip assay of 34 cytokines and discovered thymic stromal lymphopoietin (TSLP) was aberrantly expressed, which remained elevated after intravenous immunoglobulin G (IVIG) treatment and during convalescence in KD patients in comparison to healthy controls. Enzymelinked immunosorbent assay (ELISA) corroborated the upregulation of TSLP in KD patients, which was exacerbated in convalescent patients complicated with thrombosis. TSLP receptors on platelets were also significantly upregulated in KD patients complicated with thrombosis. Platelet activation, apoptosis, and mitochondrial autophagy (mitophagy) were increased in convalescence KD patients complicated with thrombosis. In vitro, TSLP induced platelet activation and platelet mitophagy in healthy blood donors, as observed in KD patients. TSLP, similar to mitophagy agonist carbonyl cyanide 3-chlorophenyl hydrazone (CCCP), promoted thrombosis, which was attenuated by the mitophagy inhibitor Mdivi-1. Co-immunoprecipitation

Platelet activation and mitophagy induction by thymic stromal lymphopoietin (TSLP) is associated with thrombosis in Kawasaki disease

“…Rick Kapur may result in thrombotic cardiovascular events. 8 The authors previously reported elevated levels of soluble CD40L and soluble P-selectin in plasma of KD patients, positively correlated with the degree of coronary artery damage. 9 In the current study they confirmed these findings, and additionally found an elevation for the platelet activation marker P-selectin, in acute KD (before and after IVIg) and convalescent patients compared to healthy controls.…”

“…In their paper, Fu and colleagues postulate that activated platelets may predispose to coronary artery lesions that may result in thrombotic cardiovascular events 8 . The authors previously reported elevated levels of soluble CD40L and soluble P‐selectin in plasma of KD patients, positively correlated with the degree of coronary artery damage 9 .…”

The crosstalk between mitochondrial quality control and metal-dependent cell death

“…Platelet activation and abnormal iron metabolism accelerated thrombosis and induced oxidative stress as well as death in the vascular wall. [ 220 , 309 , 310 ] Atherosclerosis Apoptosis, ferroptosis, pyroptosis Foam cells had abnormal lipid metabolism, and inhibition of autophagy aggravated atherosclerosis. Altering mitochondrial dynamics stimulated mitochondrial autophagy and abnormal cell proliferation of VSMCs, thereby aggravating atherosclerosis.…”

“…Through the combined action of various factors, VSMCs undergo iron overload and death, affecting vascular endothelial integrity. In addition, thymic stromal lymphopoietin is significantly elevated in patients, and it induces platelet activation via mitophagy agonists, contributing to thrombosis [ 220 ].…”