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.
Abstract:
Extracellular regulated protein kinases (ERK) signaling is a master regulator of cell behavior, life, and fate. Although ERK pathway is shown to be involved in T-cell activation, little is known about its role in the development of allograft rejection. Here, it is reported that ERK signaling pathway is activated in allograft-infiltrating T cells. On the basis of surface plasmon resonance technology, lycorine is identified as an ERK-specific inhibitor. ERK inhibition by lycorine significantly prolongs allograft survival in a stringent mouse cardiac allotransplant model. As compared to untreated mice, lycorine-treated mice show a decrease in the number and activation of allograft-infiltrated T cells. It is further confirmed that lycorine-treated mouse and human T cells are less responsive to stimulation in vitro, as indicated by their low proliferative rates and decreased cytokine production. Mechanistic studies reveal that T cells treated with lycorine exhibit mitochondrial dysfunction, resulting in metabolic reprogramming upon stimulation. Transcriptome analysis of lycorine-treated T cells reveals an enrichment in a series of downregulated terms related to immune response, the mitogen-activated protein kinase cascade, and metabolic processes. These findings offer new insights into the development of immunosuppressive agents by targeting the ERK pathway involved in T-cell activation and allograft rejection.
Insights
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.
