Role of toll-like receptor 7 (TLR7) in voluntary alcohol consumption

Abstract

Overactivation of neuroimmune signaling has been linked to excessive ethanol consumption. Tolllike receptors (TLRs) are a major component of innate immune signaling and initiate anti-and pro-inflammatory responses via intracellular signal transduction cascades. TLR7 is upregulated in post-mortem brain tissue from humans with alcohol use disorder (AUD) and animals with prior exposure to ethanol. Despite this evidence, the role of TLR7 in the regulation of voluntary ethanol consumption has not been studied. We test the hypothesis that TLR7 activation regulates voluntary ethanol drinking behavior by administering a TLR7 agonist (R848) during an intermittent access drinking procedure in mice. Acute activation of TLR7 reduced ethanol intake, preference, and total fluid intake due, at least in part, to an acute sickness response. However, chronic pre-treatment with R848 resulted in tolerance to the adverse effects of the drug and a subsequent increase in ethanol consumption. To determine the molecular machinery that mediates these behavioral changes, we evaluated gene expression after acute and chronic TLR7 activation. We found that acute TLR7 activation produces brain region specific changes in expression of immune pathway genes, whereas chronic TLR7 activation causes downregulation of TLRs and blunted cytokine induction, suggesting molecular tolerance. Our results demonstrate a novel role for TLR7 signaling in regulating voluntary ethanol consumption. Taken together, our findings suggest TLR7 may be a viable target for development of therapies to treat AUD.

Extracellular microvesicles promote microglia‐mediated pro‐inflammatory responses to ethanol

“…Though it is difficult to discern whether a single cellular disruption caused by ethanol is primarily responsible for the resultant pro-inflammatory activation, the combination of cellular insults seems to converge on the secretion of DAMP-containing MVs and subsequent induction of TLR signaling. TLR induction is a prominent feature both in human postmortem AUD brain tissue and in rodent models Grantham et al, 2020;McCarthy et al, 2017;Montesinos et al, 2016). The nature of ethanol-induced pro-inflammatory cytokine induction downstream of TLR signaling (e.g., TNF-α and IL-1β) in vivo depends on the chronicity of alcohol treatment, the brain region, and the time point that is assessed.…”

“…Pro-inflammatory immune activation in brain involves proinflammatory polarization of microglia McCarthy et al, 2018), Toll-like receptor (TLR) signaling (Alfonso-Loeches et al, 2010), and release of TLR-activating danger-associated molecular pattern molecules (DAMPs). Studies using TLR knockout mice and TLR agonists find that TLRs are involved in both gross AUD neuropathology and alcohol self-administration (Grantham et al, 2020;McCarthy et al, 2017;Pascual et al, 2011). Recently, microglia have been found to play a key role in alcohol self-administration and synaptic changes in cortex and amygdala (Warden et al, 2020).…”

The Immune System through the Lens of Alcohol Intake and Gut Microbiota

“…Interestingly, in addition to supporting neuroinflammation, TLR signaling is likely engaged in the mechanisms of regulation of the functional activity of neurotransmitter systems, which may contribute to the formation of a pathological demand for alcohol [ 106 ]. Together with TLRs activation, the production of cytokines, which can cross the blood–brain barrier (BBB), have harmful effects at CNS level [ 102 ].…”

TRAIL Mediates Neuronal Death in AUD: A Link between Neuroinflammation and Neurodegeneration

“…We have reported that TLR7 might contribute to neurodegeneration with alcohol abuse, with ethanol increasing the expression of TLR7 along with secretion of the endogenous agonist miRNA let-7b in primary ex vivo organotypic brain slice culture (OBSC) [ 10 , 13 ]. Let-7 isoforms are increased in postmortem AUD brain and in brain of mice after chronic ethanol treatment [ 14 , 15 ], and TLR7 agonism was recently found to increase alcohol self-administration [ 16 ]. Increased levels of let-7 have also been reported in the CSF of Alzheimer’s patients, suggesting that let-7/TLR7 signaling may cross multiple neurodegenerative disorder [ 17 ].…”