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Background <p>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.</p> Methods <p>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 <i>Casp1</i><sup>⁻/⁻</sup> mice and bone marrow (BM) transfer experiments.</p> Results <p>In uremic mice, circulating Ly6C⁺ monocytes decreased time-dependently. Bioinformatics identified <i>Pf</i>4 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 <i>Casp1</i> knockout, which retained intact <i>Casp11</i> expression, protected mice from PF4-exacerbated cardiac injury. BM transplantation from <i>Casp1</i><sup>⁻/⁻</sup> into wild-type mice conferred the same protective phenotype, identifying BM-derived caspase-1 as a key driver.</p> Conclusion <p>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.</p>

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

  • 期刊论文

  • 发表日期：

    2026年7月6日

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

摘要

Background

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.

Methods

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.

Results

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.

Conclusion

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.