Hyperglycemic Memory of Innate Immune Cells Promotes In Vitro Proinflammatory Responses of Human Monocytes and Murine Macrophages

J Immunol. 2021 Feb 15;206(4):807-813. doi: 10.4049/jimmunol.1901348. Epub 2021 Jan 11.


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-α 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Diabetes Mellitus, Experimental / immunology*
  • Humans
  • Hyperglycemia / immunology*
  • Immunity, Innate*
  • Immunologic Memory*
  • Inflammation / immunology
  • Macrophages / immunology*
  • Male
  • Mice