Recipient-derived macrophages mediate acute cardiac allograft rejection via GSDMD-induced pyroptosis mechanism

Abstract

Objective: To determine whether macrophage gasdermin D (GSDMD)-dependent pyroptosis drives acute cardiac allograft rejection and whether targeting GSDMD improves graft survival.

Methods: GSDMD activation was assessed by immunoblotting. Graft survival wasanalysed in global and macrophage-specific GSDMD-deficient recipients. Single-cell RNA-seq identified GSDMD-expressing populations, while immune infiltration and cytokines were measured by flow cytometry and immunohistochemistry; IL1R1 knockout and cytokine challenge were used for validation.

Results: GSDMD deficiency markedly prolonged graft survival. Single-cell profiling showed increased GSDMD expression and pyroptosis primarily in recipient-derived M1 macrophages during acute rejection. Macrophage-specific GSDMD deficiency reduced CD8⁺T cell/macrophage infiltration and decreased TNF-α and IL-1β. TNFα/IL6 activated NF-κB and JAK–STAT3 to upregulate GSDMD, and IL-1β was verified as a key effector for CD8⁺T cells mediated-rejection. GSDMD pyroptosis inhibitors mitigated rejection and extended graft survival.

Conclusion: Recipient M1 macrophages promote acute rejection via TNFα/IL6-driven NF-κB/STAT3 activation of GSDMD-mediated pyroptosis. Targeting GSDMD represents a promising strategy to enhance cardiac allograft survival.

Keywords

GSDMD / heart transplantation / macrophages / pyroptosis

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2026 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.