Hyperglycemia in stroke impairs polarization of monocytes/macrophages to a protective noninflammatory cell type

Mahtab A. Khan, Sina Schultz, Alaa Othman, Thomas Fleming, Rafael Lebrón-Galán, Dirk Rades, Diego Clemente, Peter P. Nawroth, Markus Schwaninger*

*Korrespondierende/r Autor/-in für diese Arbeit
8 Zitate (Scopus)

Abstract

Hyperglycemia iscommonin patients with acute stroke, even in those without preexisting diabetes, and denotes a bad outcome. However, the mechanisms underlying the detrimental effects of hyperglycemia are largely unclear. In a mouse model of ischemic stroke, we found that hyperglycemia increased the infarct volume and decreased the number of protective noninflammatory monocytes/macrophages in the ischemic brain. Ablation of peripheral monocytes blocked the detrimental effect of hyperglycemia, suggesting that monocytes are required. In hyperglycemic mice, α-dicarbonyl glucose metabolites, the precursors for advanced glycation end products, were significantly elevated in plasma and ischemic brain tissue. The receptor of advanced glycation end products, AGER (previously known as RAGE), interfered with polarization of macrophages to a noninflammatory phenotype. When Ager was deleted, hyperglycemia did not aggravate ischemic brain damage any longer. Independently of AGER, methylglyoxal reduced the release of endothelial CSF-1 (M-CSF), which stimulates polarization of macrophages to a noninflammatory phenotype in the microenvironment of the ischemic brain. In summary, our study identified α-dicarbonyls and AGER as mediators by which hyperglycemia lowers the number of protective noninflammatory macrophages and consequently increases ischemic brain damage. Modulating the metabolism of α-dicarbonyls or blocking AGER may improve the treatment of stroke patients with hyperglycemia.

OriginalspracheEnglisch
ZeitschriftJournal of Neuroscience
Jahrgang36
Ausgabenummer36
Seiten (von - bis)9313-9325
Seitenumfang13
ISSN0270-6474
DOIs
PublikationsstatusVeröffentlicht - 07.09.2016

Strategische Forschungsbereiche und Zentren

  • Forschungsschwerpunkt: Gehirn, Hormone, Verhalten - Center for Brain, Behavior and Metabolism (CBBM)

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