Microglial activation is not equivalent to neuroinflammation in alcohol-induced neurodegeneration: The importance of microglia phenotype

Abstract

Excessive alcohol intake, a defining characteristic of an alcohol use disorder (AUD), results in neurodegeneration in the hippocampus and entorhinal cortex that has been linked to a variety of cognitive deficits. Neuroinflammation is thought to be a factor in alcohol-induced neurodegeneration, and microglia activation is a key but not sole component of an inflammatory response. These experiments investigate the effects of ethanol exposure in a well-accepted model of an AUD on both microglial activation and blood brain barrier disruption (BBB) in order to understand their relationship to classical definitions of inflammation and alcohol-induced neurodegeneration. Following a four-day binge ethanol paradigm, rat hippocampal and entorhinal cortex tissue was examined using three distinct approaches to determine microglia phenotype and BBB disruption: immunohistochemistry, autoradiography, and ELISA. After ethanol exposure, there was an increase in [3H]-PK-11195 binding and OX-42 immunoreactivity indicative of microglial activation; however, microglia were not fully activated since both OX-6 and ED-1 immunoreactive microglia were absent. This data was supported by functional evidence as there was no increase in the proinflammatory cytokines IL-6 or TNF-α but a 26% increase in the anti-inflammatory cytokine, IL-10, and a 38% increase in the growth factor, TGF-β, seven days after exposure. Furthermore, there was no evidence of a disruption of the BBB. These data suggest that the four-day binge model of an AUD, which produces neurodegeneration in corticolimbic regions, does not elicit classical neuroinflammation but instead produces partially activated microglia. Partial activation of microglia following binge ethanol exposure suggest that microglia in this model have beneficial or homeostatic roles rather than directly contributing to neurodegeneration and are a consequence of alcohol-induced-damage instead of the source of damage.

Ganglioside accumulation in activated glia in the developing brain: comparison between WT and GalNAcT KO mice

“…While ethanol-induced microglial and astroglial activation observed in WT mice can be both benefi cial and detrimental to neuronal degeneration (70)(71)(72)(73), microglial phagocytosis is generally considered a neuroprotective process ( 74 ). Our previous and present studies indicate that activated microglia are engaged in the removal of dead neurons and thus help prevent further neurodegeneration ( 75,76 ) without inducing classical neuroinfl ammation, as demonstrated in other binge ethanol exposure models in the developing ( 4 ) and adult brain ( 77 ). Considering that ethanol induced more neurodegeneration with less elevation in the number of GFAP + cells in GalNAcT KO mice, it is possible that GFAP + GM2…”

Alcohol and Stress Activation of Microglia and Neurons: Brain Regional Effects

“…These results replicate previous studies showing an intense, 4‐day binge EtOH treatment in rats increased CD11b + IR in the hippocampus immediately following the treatment. This CD11b + IR increase declined over time, but remained persistently increased for at least 28 days (Marshall et al., 2013; McClain et al., 2011). Our studies add to this work by showing that less intense AIE treatment persistently increases CD11b in many adult brain regions.…”

“…This is consistent with chronic EtOH causing a long‐lasting “priming” of microglia, a process in which an initial stimulus causes a greater response to a secondary stimulus (Perry and Holmes, 2014). Previous studies using 4‐day binge EtOH dependence model in rats find increased CD11b + IR in the hippocampus, just after exposure, and increasing for at least 28 days (Marshall et al., 2013; McClain et al., 2011). Our studies add to this work that AIE persistently increases CD11b + IR 40 days later in adulthood.…”

Inflammation Effects on Motivation and Motor Activity: Role of Dopamine

“…First, microglia are not as 'dormant' as once believed, and are now known to have a variety of ongoing sentinel-type functions (Tremblay et al, 2011). Moreover, microglia exhibit a graded response of activation (Raivich et al, 1999), and increases in some activation markers-such as TSPO-may not indicate a true inflammatory phenotype (Marshall et al, 2013;Saijo and Glass, 2011). Consequently, the distinction between normally vs pathologically active microglia may be difficult to resolve solely on the basis of TSPO expression.…”