Heart failure & cardiomyopathies
Immune Regulation of the Liver Through the PCSK9/CD36 Pathway During Heart Transplant Rejection
Authors' conclusion
This study reveals a novel mechanism for immune regulation by the liver through the PCSK9/CD36 pathway during HTR, which influences the phenotype and function of macrophages
Study context
- Population
- Murine and human heart transplant recipients
- Comparison
- PCSK9 ablation vs intact PCSK9 in heart transplant rejection
Methodological detailsmurine and human recipients, global and hepatocyte-specific Pcsk9 knockout mice, neutralizing antibody, multiomics and single-cell RNA-sequencing
- Murine and human recipients
- Global and hepatocyte-specific Pcsk9 knockout mice
- Neutralizing antibody
- Multiomics and single-cell RNA-sequencing
Main finding
As reported in the abstract
- High serum PCSK9 levels in murine and human recipients during heart transplant rejection (HTR)
- PCSK9 ablation prolonged cardiac allograft survival and attenuated graft inflammatory cell infiltration and splenic alloreactive T-cell expansion
- PCSK9 mainly produced and significantly upregulated in recipient liver, with changes in TNF-α, IFN-γ, bile acid and fatty acid metabolism pathways
- TNF-α and IFN-γ synergistically promoted hepatocyte PCSK9 expression via SREBP2
- PCSK9 inhibited macrophage CD36 expression and fatty acid uptake and strengthened proinflammatory phenotype, promoting donor-reactive T-cell proliferation and IFN-γ production
- Protective effect of PCSK9 ablation against HTR dependent on recipient CD36 pathway
Original publication
Immune Regulation of the Liver Through the PCSK9/CD36 Pathway During Heart Transplant Rejection. Circulation. Published 26 May 2023. doi:10.
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