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Endothelin-1 (ET-1) promotes a proinflammatory microglia phenotype in diabetic conditions.

ABSTRACT: Diabetes increases the risk and severity of cognitive impairment, especially after ischemic stroke. It is also known that the activation of the endothelin (ET) system is associated with cognitive impairment and microglia around the periinfarct area produce ET-1. However, little is known about the effect of ET-1 on microglial polarization, especially under diabetic conditions. We hypothesized that (i) ET-1 activates microglia to the proinflammatory M-1-like phenotype and (ii) hypoxia/ lipopolysaccharide (LPS) activates the microglial ET system and promotes microglial activation towards the M-1 phenotype in diabetic conditions. Microglial cells (C8B4) cultured under normal-glucose (25 mmol/L) conditions and diabetes-mimicking high-glucose (50 mmol/L) conditions for 48 h were stimulated with ET-1, cobalt chloride (200 μmol/L), or LPS (100 ng/mL) for 24 h. PPET-1, ET receptor subtypes, and M1/M2 marker gene mRNA expression were measured by RT-PCR. Secreted ET-1 was measured by ELISA. A high dose of ET-1 (1 μmol/L) increases the mRNA levels of ET receptors and activates the microglia towards the M1 phenotype. Hypoxia or LPS activates the ET system in microglial cells and shifts the microglia towards the M1 phenotype in diabetic conditions. These in vitro observations warrant further investigation into the role of ET-1-mediated activation of proinflammatory microglia in post-stroke cognitive impairment in diabetes.

SUBMITTER: Abdul Y

PROVIDER: S-EPMC7483816 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Alzheimer's disease (AD) is the most common neurodegenerative disease and type 2 diabetes (T2D) plays an important role in conferring the risk for AD. Although AD and T2D share common features, the common molecular mechanisms underlying these two diseases remain elusive. METHODS:Mice with different AD- and/or tauopathy-linked genetic backgrounds (APPswe/PS1dE9, Tau P301L and APPswe/PS1dE9/Tau P301L) were fed for 6 months with standard diet or typical Western diet (TWD). After behavioral and metabolic assessments of the mice, the effects of TWD on global gene expression as well as dystrophic neurite and microglia pathology were elucidated. Consequently, mechanistic aspects related to autophagy, cell survival, phagocytic uptake as well as Trem2/Dap12 signaling pathway, were assessed in microglia upon modulation of PI3K-Akt signaling. To evaluate whether the mouse model-derived results translate to human patients, the effects of diabetic phenotype on microglial pathology were assessed in cortical biopsies of idiopathic normal pressure hydrocephalus (iNPH) patients encompassing ?-amyloid pathology. RESULTS:TWD led to obesity and diabetic phenotype in all mice regardless of the genetic background. TWD also exacerbated memory and learning impairment in APPswe/PS1dE9 and Tau P301L mice. Gene co-expression network analysis revealed impaired microglial responses to AD-related pathologies in APPswe/PS1dE9 and APPswe/PS1dE9/Tau P301L mice upon TWD, pointing specifically towards aberrant microglial functionality due to altered downstream signaling of Trem2 and PI3K-Akt. Accordingly, fewer microglia, which did not show morphological changes, and increased number of dystrophic neurites around ?-amyloid plaques were discovered in the hippocampus of TWD mice. Mechanistic studies in mouse microglia revealed that interference of PI3K-Akt signaling significantly decreased phagocytic uptake and proinflammatory response. Moreover, increased activity of Syk-kinase upon ligand-induced activation of Trem2/Dap12 signaling was detected. Finally, characterization of microglial pathology in cortical biopsies of iNPH patients revealed a significant decrease in the number of microglia per ?-amyloid plaque in obese individuals with concomitant T2D as compared to both normal weight and obese individuals without T2D. CONCLUSIONS:Collectively, these results suggest that diabetic phenotype in mice and humans mechanistically associates with abnormally reduced microglial responses to ?-amyloid pathology and further suggest that AD and T2D share overlapping pathomechanisms, likely involving altered immune function in the brain.

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Endothelin-1 (ET-1) promotes a proinflammatory microglia phenotype in diabetic conditions.

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