ERK Inhibition Promotes Engraftment of Allografts by Reprogramming T-Cell Metabolism
Xiaosheng Tan1,2,3,4, Changxing Qi5, Xiangli Zhao1,2,3,4
1Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, Hubei Province, 430030, P. R. China.
Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|April 4, 2023
Summary
Lycorine inhibits the ERK signaling pathway, a key regulator of T-cell activation. This inhibition prolongs allograft survival by reducing T-cell infiltration and activation in transplanted organs.
Area of Science:
- Immunology
- Cell Biology
- Pharmacology
Background:
- Extracellular regulated protein kinases (ERK) signaling regulates cell behavior and T-cell activation.
- The role of the ERK pathway in allograft rejection remains largely unknown.
Purpose of the Study:
- To investigate the role of ERK signaling in allograft rejection.
- To identify potential therapeutic targets for immunosuppression.
Main Methods:
- Surface plasmon resonance technology to identify ERK inhibitors.
- Cardiac allotransplantation mouse model to assess allograft survival.
- In vitro T-cell stimulation assays to evaluate proliferation and cytokine production.
- Mitochondrial function assays and transcriptome analysis.
Main Results:
- ERK signaling is activated in T cells infiltrating allografts.
- Lycorine identified as a specific ERK inhibitor, significantly prolonging allograft survival.
- Lycorine treatment reduced T-cell infiltration, activation, proliferation, and cytokine production.
- Lycorine induced mitochondrial dysfunction and metabolic reprogramming in T cells.
Conclusions:
- Targeting the ERK pathway with lycorine is a promising strategy for immunosuppression.
- Lycorine's mechanism involves T-cell metabolic reprogramming and reduced immune response.
- These findings provide novel insights into combating allograft rejection.
