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Background: Many brain disorders, including alcohol use disorder (AUD), are associated with induction of multiple proinflammatory genes. One aspect of proinflammatory signaling is progressive increases in expression across cells and induction of other innate immune genes. High‐mobility group box 1 (HMGB1) heteromers contribute to amplification by potentiating multiple proinflammatory responses, including Toll‐like receptors (TLRs). TLR signaling recruits coupling proteins linked to nuclear transcription factors that induce proinflammatory cytokines and chemokines and their respective receptors. We tested the hypothesis that AUD induction of TLR expression increases levels of proinflammatory genes and cellular signaling cascades in association with neurodegeneration in the orbitofrontal cortex (OFC). Methods: Postmortem human OFC tissue samples (n = 10) from males diagnosed with AUD were compared to age‐matched moderate drinking controls (CON). Neuroimmune signaling molecules were assessed using immunohistochemistry for protein and reverse transcription polymerase chain reaction for messenger RNA (mRNA). Results: In the AUD OFC, we report induction of the endogenous TLR agonist HMGB1 as well as all TLRs assessed (i.e., TLR2‐TLR9) except TLR1. This was accompanied by increased expression of the TLR adaptor protein myeloid differentiation primary response 88 (MyD88), activation of the proinflammatory nuclear transcription factor nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NFκB), and downstream induction of proinflammatory cytokines, chemokines, and their corresponding receptors. Several of these proinflammatory signaling markers are expressed in glia and neurons. The induction of HMGB1‐TLR‐MyD88‐NFκB proinflammatory signaling pathways correlates with neurodegeneration (i.e., Fluoro‐Jade B), lifetime alcohol consumption, and age of drinking onset. Conclusion: These data implicate the induction of HMGB1‐TLR‐MyD88‐NFκB cascades through coordinated glial and neuronal signaling as contributors to the neurodegeneration seen in the postmortem human OFC of individuals with AUD. [ABSTRACT FROM AUTHOR]

Background: Toll‐like receptor 7 (TLR7) is an endosomal TLR that is activated by single‐stranded RNA, including endogenous microRNAs (e.g., let‐7b). Increased hepatic expression of TLRs, microRNAs, and inflammatory mediators is linked to ethanol (EtOH) exposure and to alcoholic liver disease (ALD). ALD invovles chronic hepatic inflammation that can progress to alcoholic hepatitis (AH), a particularly severe form of ALD. This study aimed to investigate TLR7 expression in patients with different liver disease phenotypes and in mouse liver following alcohol exposure. Methods: Hepatic mRNA expression was determined by RNA sequencing of liver tissue from patients with liver disease or normal liver tissue. Mice were exposed to subchronic EtOH followed by administration of the TLR7 agonist imiquimod. Primary human hepatocytes were exposed to EtOH or imiquimod in vitro. Results: RNAseq analysis revealed that hepatic expression of TLR7 and let‐7b microRNA, an endogenous TLR7 ligand, was significantly increased in AH patients. Hepatic expression of TLR7 and let‐7b positively correlated with hepatic IL‐8 mRNA expression. In mice, EtOH increased hepatic TLR7 mRNA expression and enhanced imiquimod‐induced expression of the pro‐inflammatory mediators TNFα, MCP‐1, and iNOS. In vitro, EtOH significantly increased hepatocyte TLR7 mRNA and the TLR7 agonist, imiquimod, induced hepatocyte expression of TNFα and IL‐8 mRNA. EtOH also increased the release of let‐7b in microvesicles from hepatocytes, suggesting that EtOH can increase the expression of both the receptor and its endogenous ligand. Conclusions: These studies suggest that increased TLR7 signaling caused by increased expression of TLR7 and its endogenous ligand let‐7b may contribute to the enhanced inflammatory response associated with AH. Activation of the RNA receptor, Toll‐like Receptor 7, by endogenous microRNA let‐7 contributes to alcoholic hepatitis (AH). Steatohepatitis (fatty liver) involves chronic mild proinflammatory signaling through Toll‐like receptor 4 by LPS‐endotoxin. Some patients spontaneously progress to acute alcoholic hepatitis, a sometimes fatal, serious systemic immune response syndrome. This study finds Toll‐like receptor 7, an RNA receptor, responds to endogenous let‐7 microRNAs, uniquely amplify key proinflammatory genes in patients with AH. [ABSTRACT FROM AUTHOR]