期刊
FRONTIERS IN IMMUNOLOGY
卷 14, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2023.1018076
关键词
Fasciola hepatica; helminth defence molecule; macrophage; immunometabolism; glutaminolysis; immune regulation; alpha-ketoglutarate (alpha-KG); fatty acid oxidation (FAO)
类别
We have discovered a peptide called FhHDM-1 in the secretions of the liver fluke, which can regulate inflammation by reprogramming macrophage metabolism. Specifically, FhHDM-1 switches macrophage metabolism to rely on oxidative phosphorylation fueled by fatty acids and supported by the induction of glutaminolysis. This metabolic switch leads to a decrease in TNF and IL-6 production, indicating the potential of FhHDM-1 in preventing inflammation.
We have previously identified an immune modulating peptide, termed FhHDM-1, within the secretions of the liver fluke, Fasciola hepatica, which is sufficiently potent to prevent the progression of type 1 diabetes and multiple sclerosis in murine models of disease. Here, we have determined that the FhHDM-1 peptide regulates inflammation by reprogramming macrophage metabolism. Specifically, FhHDM-1 switched macrophage metabolism to a dependence on oxidative phosphorylation fuelled by fatty acids and supported by the induction of glutaminolysis. The catabolism of glutamine also resulted in an accumulation of alpha ketoglutarate (alpha-KG). These changes in metabolic activity were associated with a concomitant reduction in glycolytic flux, and the subsequent decrease in TNF and IL-6 production at the protein level. Interestingly, FhHDM-1 treated macrophages did not express the characteristic genes of an M2 phenotype, thereby indicating the specific regulation of inflammation, as opposed to the induction of an anti-inflammatory phenotype per se. Use of an inactive derivative of FhHDM-1, which did not modulate macrophage responses, revealed that the regulation of immune responses was dependent on the ability of FhHDM-1 to modulate lysosomal pH. These results identify a novel functional association between the lysosome and mitochondrial metabolism in macrophages, and further highlight the significant therapeutic potential of FhHDM-1 to prevent inflammation.
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