# Dextrorotatory kynurenine suppresses acute rejection through inhibiting M1 macrophage-mediated inflammation

## TL;DR

D-Kyn, a dextrorotatory amino acid, suppresses inflammation in transplants by inhibiting M1 macrophages, offering a potential treatment for acute rejection.

## Contribution

D-Kyn is shown to be more effective than L-Kyn in suppressing M1 macrophage-driven inflammation through specific pathways.

## Key findings

- D-Kyn levels correlate with stable graft function in transplant recipients.
- D-Kyn inhibits M1 macrophage inflammation via the PHGDH/TLR4/Caspase-1 pathway.
- D-Kyn treatment reduces AR progression in murine skin and kidney transplants.

## Abstract

Acute rejection (AR) remains a critical challenge to graft survival in kidney transplantation. Although dextrorotatory-amino acids (D-AAs) have been recognized as biologically active compounds, their role in mediating immunosuppression was poorly depicted. To address this, serum samples from renal transplant recipients were analyzed via [d0]/[d5]-estradiol-3-benzoate-17β-chloroformate (17β-EBC) based ion mobility-mass spectrometry (IM-MS) to assess D-AAs levels. scRNA-seq data from the GSE109564 dataset were analyzed. Additionally, murine skin and kidney transplantation models were utilized to assess the in vivo impact of d-kynurenine (D-Kyn) treatment on AR. Through analysis of patient serum and murine transplantation models, we identified D-Kyn as a key metabolite whose elevated levels correlate with stable graft function. We found that D-Kyn, more effectively than its chiral counterpart L-Kyn, inhibits the inflammatory activity of M1 macrophages. This suppression is mediated via the PHGDH/TLR4/Caspase-1 pathway, reducing the transcription and secretion of inflammatory cytokines. In murine models of skin and kidney transplantation, D-Kyn treatment demonstrated potent immunosuppressive effects, attenuating macrophage-mediated inflammation and CD8 + T cell activation, potentially through regulation of macrophage-derived IL-23a. Our findings reveal D-Kyn as a promising therapeutic candidate for preventing acute rejection and improving transplant outcomes and lay the foundation for future clinical applications from the perspective of dextrorotatory amino acids.

New research suggests that D-Kyn could become a novel therapeutic target for preventing or treating acute rejection (AR) in transplant patients.

D-Kyn suppresses pro-inflammatory M1 macrophages—key drivers of AR—by blocking the pathway (PHGDH/TLR4/Caspase-1) that triggers damaging signals.D-Kyn is more effective than its “left-handed” counterpart (L-Kyn) in reducing inflammation.In mouse skin transplant models, D-Kyn treatment reduced AR progression and inflammation by taming M1 macrophages and their activation of destructive immune cells (CD8 T cells).D-Kyn significantly ameliorated AR progression in murine kidney transplants by suppressing key inflammatory pathways, particularly macrophage activation via the TLR4/ERK1/2/NLRP3 inflammasome axis, and by reducing cytokine release and CD8 T cell infiltration.

D-Kyn suppresses pro-inflammatory M1 macrophages—key drivers of AR—by blocking the pathway (PHGDH/TLR4/Caspase-1) that triggers damaging signals.

D-Kyn is more effective than its “left-handed” counterpart (L-Kyn) in reducing inflammation.

In mouse skin transplant models, D-Kyn treatment reduced AR progression and inflammation by taming M1 macrophages and their activation of destructive immune cells (CD8 T cells).

D-Kyn significantly ameliorated AR progression in murine kidney transplants by suppressing key inflammatory pathways, particularly macrophage activation via the TLR4/ERK1/2/NLRP3 inflammasome axis, and by reducing cytokine release and CD8 T cell infiltration.

New research suggests that D-Kyn could become a novel therapeutic target for preventing or treating acute rejection (AR) in transplant patients.