| Autor: |
Fitzgerald HK; School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, D02 R590 Dublin, Ireland., O'Rourke SA; School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, D02 R590 Dublin, Ireland.; Trinity Centre for Biomedical Engineering, Trinity Biomedical Sciences Institute, Trinity College Dublin, D02 R590 Dublin, Ireland., Desmond E; School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, D02 R590 Dublin, Ireland., Neto NGB; Trinity Centre for Biomedical Engineering, Trinity Biomedical Sciences Institute, Trinity College Dublin, D02 R590 Dublin, Ireland., Monaghan MG; Trinity Centre for Biomedical Engineering, Trinity Biomedical Sciences Institute, Trinity College Dublin, D02 R590 Dublin, Ireland., Tosetto M; Centre for Colorectal Disease, St. Vincent's University Hospital, School of Medicine, University College Dublin, D04 YN26 Dublin, Ireland., Doherty J; Centre for Colorectal Disease, St. Vincent's University Hospital, School of Medicine, University College Dublin, D04 YN26 Dublin, Ireland., Ryan EJ; Department of Biological Sciences, Health Research Institute, University of Limerick, V94 T9PX Limerick, Ireland., Doherty GA; Centre for Colorectal Disease, St. Vincent's University Hospital, School of Medicine, University College Dublin, D04 YN26 Dublin, Ireland., Nolan DP; School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, D02 R590 Dublin, Ireland., Fletcher JM; School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, D02 R590 Dublin, Ireland.; School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, D02 R590 Dublin, Ireland., Dunne A; School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, D02 R590 Dublin, Ireland.; School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, D02 R590 Dublin, Ireland. |
| Abstrakt: |
The extracellular parasite and causative agent of African sleeping sickness Trypanosoma brucei ( T. brucei ) has evolved a number of strategies to avoid immune detection in the host. One recently described mechanism involves the conversion of host-derived amino acids to aromatic ketoacids, which are detected at relatively high concentrations in the bloodstream of infected individuals. These ketoacids have been shown to directly suppress inflammatory responses in murine immune cells, as well as acting as potent inducers of the stress response enzyme, heme oxygenase 1 (HO-1), which has proven anti-inflammatory properties. The aim of this study was to investigate the immunomodulatory properties of the T. brucei -derived ketoacids in primary human immune cells and further examine their potential as a therapy for inflammatory diseases. We report that the T. brucei -derived ketoacids, indole pyruvate (IP) and hydroxyphenylpyruvate (HPP), induce HO-1 expression through Nrf2 activation in human dendritic cells (DC). They also limit DC maturation and suppress the production of pro-inflammatory cytokines, which, in turn, leads to a reduced capacity to differentiate adaptive CD4 + T cells. Furthermore, the ketoacids are capable of modulating DC cellular metabolism and suppressing the inflammatory profile of cells isolated from patients with inflammatory bowel disease. This study therefore not only provides further evidence of the immune-evasion mechanisms employed by T. brucei , but also supports further exploration of this new class of HO-1 inducers as potential therapeutics for the treatment of inflammatory conditions. |
