期刊
JOURNAL OF IMMUNOLOGY
卷 206, 期 4, 页码 807-813出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1901348
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资金
- European Research Council [310372]
- Netherlands Organization for Scientific Research [91616083]
- Dutch Diabetes Research Foundation [2015.82.1824]
- Dutch Heart Foundation (IN-CONTROL)
Research suggests that high blood sugar levels may induce trained immunity, leading to inflammation and increasing the risk of diabetes-related complications in patients.
It has been well established that the presence of diabetes is accompanied by a chronic inflammatory state promoting various diabetes-associated complications. One potential driver of this enhanced inflammatory state in patients with diabetes is hyperglycemia. Even after blood glucose control is achieved, diabetes-associated complications persist, suggesting the presence of a hyperglycemic memory. Innate immune cells, critically involved in various complications associated with diabetes, can build nonspecific, immunological memory (trained immunity) via epigenetic regulation. We examine the potential involvement of hyperglycemia-induced trained immunity in promoting inflammation. Our results show that hyperglycemia induces a trained phenotype in vivo in mice and in vitro in human monocytes, representative by an increased TNF-alpha secretion after ex vivo stimulation with LPS. These effects were largely mediated by epigenetic changes controlled by the mixed lineage leukemia (MLL) family because treatment with the MLL inhibitor menin-MLL during the process of trained immunity acquisition repressed the proinflammatory phenotype. Collectively, our results identify a novel link between hyperglycemia and inflammation in innate immune cells that might explain the increased proinflammatory state during diabetes potentially contributing to the development of various diabetes-associated complications.
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