Hung over? Maybe it’s your overactive microglia

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Science Translational Medicine  17 May 2017:
Vol. 9, Issue 390, eaan4287
DOI: 10.1126/scitranslmed.aan4287


Acute ethanol intake is associated with a mild suppression of microglial activity followed by a more robust inflammatory reaction during the withdrawal period.

Acute alcohol intoxication has broad implications for public health ranging from being a leading cause of accidental deaths to more minor issues, such as hangovers. Recent studies have shown that alcohol consumption is associated with neuroinflammation and that this effect may be an important cause of neuronal dysfunction and neurodegeneration. The mechanism of alcohol-related neuroinflammation has not been well characterized. Using in vitro mouse microglial cell culture and in vivo mouse models, Walter et al. examined the effect of acute binge ethanol and withdrawal on microglial activity and production of inflammatory mediators.

C57BL/6J mice were given high-dose ethanol intragastrically to mimic binge drinking. Blood alcohol concentration (BAC), microglial markers, pro- and anti-inflammatory cytokine mRNA expression, and protein levels were measured in mouse brains at 1, 6, 12, and 18 hours after ethanol administration. The main finding was that microglial activity exhibited a time-dependent biphasic modulation: After an initial suppression (1 to 6 hours after ethanol), expression of the microglial markers CD68 and Iba1 increased (12 to 24 hours after ethanol). Concurrently measured proinflammatory cytokines tumor necrosis factor–α (TNFα) and Ccl2 followed the same pattern, suggesting that increased inflammation occurred during alcohol withdrawal. Anti-inflammatory cytokine levels also increased during alcohol withdrawal.To determine whether the change in inflammatory response was from microglial activity, additional experiments were performed in microglia-depleted mice (treated with CSF1R inhibitor PLX5622). Microglial depletion before ethanol administration led to a decrease in ethanol withdrawal–associated inflammation by decreasing TNFα and Ccl2 expression. Additionally, there was an associated enhancement of anti-inflammatory cytokines lL-1ra and interleukin-4. These results suggest that microglial depletion partially blunts the acute binge withdrawal proinflammatory gene response and enhances the anti-inflammatory response.

There are several interesting findings in this paper, including the description of the time course of microglial activation after acute binge ethanol consumption and that microglial depletion blunted the proinflammatory effects while enhancing the anti-inflammatory effects of alcohol withdrawal. Importantly, they found that microglia depletion had only a partial effect on alcohol withdrawal–associated inflammation, suggesting that there are other cell populations also contributing to alcohol related neuroinflammation.

The high alcohol concentrations in this murine study (more than 400 mg/dL BAC from 6 g/kg of alcohol) limit application of these findings to humans; a translational study examining microglial activity in humans with acute alcohol intoxication—perhaps using PET imaging—would validate these animal studies. A future study might consider looking at repeated binge drinking episodes and their long-term effects.

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