Hyperglycemic memory of innate immune cells promotes in vitro proinflammatory responses of human monocytes and murine macrophages

Kathrin Thiem*, Samuel T. Keating, Mihai G. Netea, Niels P. Riksen, Cees J. Tack, Janna van Diepen, Rinke Stienstra

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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-a 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.

Original languageEnglish
Pages (from-to)807-813
Number of pages7
JournalJournal of Immunology
Volume206
Issue number4
DOIs
Publication statusPublished - 15 Feb 2021

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