Increased Toll‐like Receptor‐MyD88‐NFκB‐Proinflammatory neuroimmune signaling in the orbitofrontal cortex of humans with alcohol use disorder

Abstract

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 Tolllike 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.

NADPH oxidase and endoplasmic reticulum stress is associated with neuronal degeneration in orbitofrontal cortex of individuals with alcohol use disorder

“…Expression of caspase 12 similarly positively correlates with expression of ER stress‐associated proteins and colocalizes with the NADPH oxidase NOX2. These data are consistent with concerted activation of oxidative stress and ER stress pathways within the same cell leading to cell death‐associated caspase cascades, which could contribute to the observed neuronal cell death in the OFC of individuals with AUD 1,3,7 . Indeed, in a prior study, we reported increased colocalization of the neuronal marker NeuN with the cell death marker Fluoro‐Jade B in OFC tissue samples from the same individuals used in the present investigation indicative of increased neuronal cell death in the post‐mortem human OFC of individuals with AUD 1 .…”

Multi-omics signatures of alcohol use disorder in the dorsal and ventral striatum

“…On a phenotypic level, there is also widespread overlap between symptoms of inflammation and of SUDs, such as anhedonia, depression, and decreased cognitive functioning [ 58 ]. In addition, in candidate gene studies in postmortem human PFC, hippocampus, and orbitofrontal cortex, increased mRNA levels of HMGB1 , which encodes a proinflammatory cytokine and toll-like receptor genes have been associated with alcohol consumption in AUD cases, providing evidence for chronic neuroinflammation in response to alcohol [ 59 – 61 ]. Notably, there is an overlap of findings not only on the single-gene level but also on the level of pathways and networks/modules.…”

The Toll‐like receptor 7 agonist imiquimod increases ethanol self‐administration and induces expression of Toll‐like receptor related genes

“…While studies have found increased expression of multiple TLRs in post‐mortem human brain of AUD patients, 16 preclinical studies indicate a complex relationship with alcohol drinking. An initial experiment linking TLRs to alcohol consumption found that the TLR4 agonist and bacterial endotoxin LPS increased voluntary intake of alcohol in a two‐bottle choice model in multiple mouse strains 17 .…”