Microglial-derived miRNA let-7 and HMGB1 contribute to ethanol-induced neurotoxicity via TLR7

Abstract

BackgroundToll-like receptor (TLR) signaling is emerging as an important component of neurodegeneration. TLR7 senses viral RNA and certain endogenous miRNAs to initiate innate immune responses leading to neurodegeneration. Alcoholism is associated with hippocampal degeneration, with preclinical studies linking ethanol-induced neurodegeneration with central innate immune induction and TLR activation. The endogenous miRNA let-7b binds TLR7 to cause neurodegeneration.MethodsTLR7 and other immune markers were assessed in postmortem human hippocampal tissue that was obtained from the New South Wales Tissue Bank. Rat hippocampal-entorhinal cortex (HEC) slice culture was used to assess specific effects of ethanol on TLR7, let-7b, and microvesicles.ResultsWe report here that hippocampal tissue from postmortem human alcoholic brains shows increased expression of TLR7 and increased microglial activation. Using HEC slice culture, we found that ethanol induces TLR7 and let-7b expression. Ethanol caused TLR7-associated neuroimmune gene induction and initiated the release let-7b in microvesicles (MVs), enhancing TLR7-mediated neurotoxicity. Further, ethanol increased let-7b binding to the danger signaling molecule high mobility group box-1 (HMGB1) in MVs, while reducing let-7 binding to classical chaperone protein argonaute (Ago2). Flow cytometric analysis of MVs from HEC media and analysis of MVs from brain cell culture lines found that microglia were the primary source of let-7b and HMGB1-containing MVs.ConclusionsOur results identify that ethanol induces neuroimmune pathology involving the release of let-7b/HMGB1 complexes in microglia-derived microvesicles. This contributes to hippocampal neurodegeneration and may play a role in the pathology of alcoholism.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-017-0799-4) contains supplementary material, which is available to authorized users.

Chronic ethanol consumption: role of TLR3/TRIF‐dependent signaling

“…TLR3 and TLR7) or the TRIF-dependent pathway is targeted by alcohol, recent studies suggest that alcohol increases expression of endogenous ligands (HMGB1 and miRNAs) that may preferentially target specific TLRs (Crews et al . 2013; Coleman et al . 2017).…”

The role of neuroimmune signaling in alcoholism

“…Interestingly, members of the miRNA let-7 family were induced across species. Recently, ethanol has been found to potentiate TLR7-mediated neurotoxicity via release of let-7 in MVs (Coleman et al, 2017). The miR-155 is also found in vesicles and promotes TLR4 associated neuroimmune responses after chronic ethanol (Lippai et al, 2013a).…”

“…Recurrent and persistent NF-κB activation by repeated alcohol consumption appears to mimic a chronic inflammatory state. This is evidenced by increased innate immune markers in the post-mortem brains of human alcoholics (Coleman et al, 2017; Crews et al, 2013a) Further, NF-κB target genes are upregulated in the prefrontal cortex of alcoholics (Okvist et al, 2007). This persistent and chronic immune response has also been seen after one dose of systemic LPS.…”

“…This amplifies immune responses in an autocrine and paracrine fashion, as secreted DAMPs and cytokines activate both their cell of origin and surrounding cells (Figure 6). Paracrine signaling induced by ethanol also proceeds through the release of pro-inflammatory miRNA-containing microvesicles (Bala et al, 2011; Coleman et al, 2017; Szabo and Lippai, 2014). This method of intercellular paracrine signaling has been implicated in many conditions such as cancer, cardiovascular disease, and neurodegeneration (Hulsmans and Holvoet, 2013; Lehmann et al, 2012a; Ohshima et al, 2010).…”

New Implications for the Melanocortin System in Alcohol Drinking Behavior in Adolescents: The Glial Dysfunction Hypothesis

“…From this angle and given their inflammatory properties, microglia arise as crucial players in the onset and progression of alcohol-induced neuronal dysfunction and behavioral abnormalities (Chastain and Sarkar, 2014; Yang et al, 2014; Suk, 2007). Considerable evidence has described that ethanol triggers microglial activation in cell cultures (Fernandez-Lizarbe et al, 2009; Alfonso-Loeches et al, 2010; Boyadjieva and Sarkar, 2010, 2013; Fernandez-Lizarbe et al, 2013; Alfonso-Loeches et al, 2016), animal models (Alfonso-Loeches and Guerri, 2011; McClain et al, 2011; Qin and Crews, 2012a; Zhao et al, 2013; Ahlers et al, 2015; Alfonso-Loeches et al, 2016) and postmortem brains of alcoholics (He and Crews, 2008; Byun et al, 2014; Coleman et al, 2017). Indeed, ethanol increases the number of microglia showing large cell bodies and thick processes characteristic of activated morphology (Nixon et al, 2008; Fernandez-Lizarbe et al, 2009; McClain et al, 2011; Ahlers et al, 2015) and most of these changes are accompanied with elevated expression of pro-inflammatory cytokines, including TNF-α, MCP-1, and IL-1β, as well as neuronal damage (Alfonso-Loeches and Guerri, 2011; Boyadjieva and Sarkar, 2013; Lippai et al, 2013a; Zhao et al, 2013; Byun et al, 2014; Coleman et al, 2017).…”