TSLP induces platelet mitophagy and promotes thrombosis in Kawasaki disease
Bibliographic record
Abstract
Abstract Background Kawasaki disease (KD) is an acute systemic vasculitis primarily affecting infants and children with an unclear etiology. Coronary artery aneurysm (CAA) is a common manifestation in severe KD patents, which may lead to thrombotic cardiovascular events such as heart attack and stroke even years after onset. We and others have previously reported systemic platelet activation in KD patients. Thymic stromal lymphopoietin (TSLP) is a recently identified interleukin-7 (IL-7) like cytokine associated with promoting pathological inflammation and most notably, platelet activation. The present study is to investigate the role of TSLP in KD-associated thrombosis. Methods To discover potential proteins underlying platelet activation in KD, we conducted a protein chip assay of 34 cytokines and discovered a significant upregulation in thymus stromal lymphopoietin (TSLP). ELISA corroborated the upregulation of TSLP in another group of KD patients. Clinical samples (plasma and platelets) from KD patients and healthy controls were analyzed via flow cytometry, immunofluorescent confocal microscopy, western blot, immunoprecipitation and thrombosis assays to reveal the underlying mechanisms. Results Among the 34 cytokines, we discovered several were aberrantly expressed, nine of which were continuously elevated after IVIG treatment and maintained during the convalescence in KD patients compared to healthy controls, including TSLP. The upregulation of TSLP in KD patients was confirmed by ELISA, which showed a further increase of TSLP in convalescent patients complicated with thrombosis. The expression of TSLP receptors (TSLPRs) on platelets were also significantly upregulated in KD patients complicated with thrombosis. Platelet activation, apoptosis, and mitochondrial autophagy (mitophagy) were increased in KD patients, which increase was exacerbated in convalescent patients complicated with thrombosis. In vitro, TSLP induced platelet activation and platelet mitophagy in healthy blood donors as we observed in KD patients. TSLP, similar to mitophagy agonist CCCP, promoted thrombosis, which was attenuated by the mitophagy inhibitor Mdivi-1. Co-immunoprecipitation in TSLP-treated platelets revealed TSLPR bound to mitophagy regulators, Parkin and VDAC1, suggesting a potential novel TSLP-mediated platelet mitophagy pathway. Conclusions Our results demonstrate that TSLP induces platelet mitophagy via a novel TSLPR/Parkin/VDAC1 mitophagy pathway that promotes thrombosis in KD. These results suggest TSLP as a novel therapeutic target against KD-associated thrombosis.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".