Activation of Macrophages and Microglia by Interferon-γ and Lipopolysaccharide Increases Methylglyoxal Production: A New Mechanism in the Development of Vascular Complications and Cognitive Decline in Type 2 Diabetes Mellitus?

Karthik Dhananjayan, Dhanushka Gunawardena, Nerissa L Hearn, Tanja Sonntag, Chris Moran, Erika Gyengesi, Velandai Srikanth, Gerald Münch

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7 Citations (Scopus)

Abstract

Methylglyoxal (MGO), a dicarbonyl compound derived from glucose, is elevated in diabetes mellitus and contributes to vascular complications by crosslinking collagen and increasing arterial stiffness. It is known that MGO contributes to inflammation as it forms advanced glycation end products (AGEs), which activate macrophages via the receptor RAGE. The aim of study was to investigate whether inflammatory activation can increase MGO levels, thereby completing a vicious cycle. In order to validate this, macrophage (RAW264.7, J774A.1) and microglial (N11) cells were stimulated with IFN-γ and LPS (5+5 and 10+10 IFN-γ U/ml or μg/ml LPS), and extracellular MGO concentration was determined after derivatization with 5,6-Diamino-2,4-dihydroxypyrimidine sulfate by HPLC. MGO levels in activated macrophage cells (RAW264.7) peaked at 48h, increasing 2.86-fold (3.14±0.4 μM) at 5 U/ml IFN-γ5 μg/ml LPS, and 4.74-fold (5.46±0.30 μM) at 10 U/ml IFN-γ10 μg/ml LPS compared to the non-activated controls (1.15±0.02 μM). The other two cell lines, J774A.1 macrophages and N11 microglia, showed a similar response. We suggest that inflammation increases MGO production, possibly exacerbating arterial stiffness, cardiovascular complications, and diabetes-related cognitive decline.

Original languageEnglish
Pages (from-to)467-479
Number of pages13
JournalJournal of Alzheimer's Disease
Volume59
Issue number2
DOIs
Publication statusPublished - 2017

Keywords

  • , vascular complications
  • Cognitive decline
  • inflammation
  • methylglyoxal
  • type 2 diabetes mellitus

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