Immune-Mediated Necrotic Cell Death Initiated by Stressed Cardiomyocytes is a Major Contributor to Cardiomyocyte Loss Following Myocardial Infarction
Discuss this preprint
Start a discussion What are Sciety discussions?Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
Aims
Percutaneous coronary intervention has improved survival following myocardial infarction, yet strategies to further reduce infarct size are limited. This study investigates the role of cytotoxic γδ-T cells in ischemic cardiomyocyte death and potential therapeutic interventions to reduce infarct size.
Methods
Genetic and pharmacological approaches were used to delete γδ-T cells and their specific proteins to assess their involvement in cardiomyocyte death using mouse models of permanent ligation (PL) and ischemia/reperfusion (IR).
Results
γδ-T cells accumulated in infarct zones within 6h post-PL, expressing IFN-γ, TNF-α, granzyme B, and perforin. Their deletion reduced infarct size by 73% (PL) and 64% (IR). They induced cardiomyocyte death via apoptosis, gasdermin E-dependent pyroptosis, and MLKL-dependent necroptosis; γδ-T cell depletion reduced apoptosis by 80% and pyroptosis by 38%, with perforin deletion yielding similar effects. Necroptosis, attributed to combined IFN-γ/TNF-α cytotoxicity, decreased by 67%. Cytoplasmic DNA (cDNA) in stressed cardiomyocytes activated the cGAS/STING pathway, inducing expression of chemoattractant MCP-1 and death signal RAE-1. These signals recruited and activated γδ-T cells, which then triggered the death of the stressed cardiomyocytes. STING inhibition suppressed these expressions, reducing γδ-T cell accumulation and infarct size. NKG2D-deficient γδ-T cells prevented activation and reduced infarct size. Administration of an anti-IFNAR antibody at PL onset markedly reduced infarct size.
Conclusion
Early activation of cytotoxic γδ-T cells via cardiomyocyte stress signals contributes significantly to immunogenic cardiomyocyte death. Targeting the STING pathway and type I interferon signalling presents a promising therapeutic avenue to mitigate infarct size and improve outcomes.
