A platelet-monocyte pyroptotic axis mediates uremic cardiomyopathy: critical role of PF4 and hematopoietic caspase-1.

Authors

Yang Yang, Minyu Zhang, Meihan Chen, Xiaomeng Li, Jing Xu, Ti Zhang, Dongjuan Zhang, Deyang Kong, Lu Ma, Ai Peng, Changlin Mei

Published in

Inflammation research : official journal of the European Histamine Research Society ... [et al.]. Volume 75. Issue 1. Jul 06, 2026. Epub Jul 06, 2026.

Abstract

Cardiovascular disease is the leading cause of death in end-stage renal disease (ESRD). While platelet activation and monocyte inflammation are hallmarks of uremia, how platelet-derived factors drive monocyte-mediated cardiac remodeling remains elusive. We investigated the role of platelet factor-4 (PF4) in monocyte pyroptosis and its contribution to uremic cardiomyopathy.
A uremic mouse model was established by 5/6 nephrectomy (Nx). Differentially expressed genes between Ly6C⁺ and Ly6C⁻ monocyte subsets were identified by microarray and WGCNA. PF4 effects were assessed by systemic administration with or without CXCR3 inhibition or PF4 neutralization. Caspase-1 activation was evaluated by FAM-FLICA staining and IL-1β ELISA. The role of caspase-1 was examined using global Casp1^⁻/⁻ mice and bone marrow (BM) transfer experiments.
In uremic mice, circulating Ly6C⁺ monocytes decreased time-dependently. Bioinformatics identified Pf4 as a key hub gene, with six pyroptosis-associated genes upregulated in Ly6C⁺ monocytes versus sham controls. PF4 infusion, at least in part through CXCR3, shortened Ly6C⁺ monocyte lifespan, upregulated pyroptosis-related genes, increased active caspase-1⁺ cells and IL-1β release, and accelerated cardiac dysfunction and fibrosis. CXCR3 inhibition or PF4 neutralization attenuated these effects. Global Casp1 knockout, which retained intact Casp11 expression, protected mice from PF4-exacerbated cardiac injury. BM transplantation from Casp1^⁻/⁻ into wild-type mice conferred the same protective phenotype, identifying BM-derived caspase-1 as a key driver.
Our study identifies a pathway where PF4, acting partly through CXCR3, contributes to caspase-1-dependent pyroptosis in Ly6C⁺ monocytes, driving pathological cardiac remodeling in uremia. Targeting this axis in BM-derived cells may represent a therapeutic strategy for heart failure in ESRD.

PMID:
42406141
Bibliographic data and abstract were imported from PubMed on 06 Jul 2026.

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