TABLE 1.
Select articles on HMGB1, adolescence, and alcohol.
| Preclinical and clinical alcohol exposure effects on HMGB1 primary literature | ||||
|---|---|---|---|---|
| Species | Exposure | Assessment | Results | Reference |
| Rat (Wistar) | AIE | Prefrontal cortex (PL, IL) | ↑ HMGB1 (IHC, mRNA), also TLR4, TLR3 (mRNA) in P56 and P80 adult rats. HMGB1 colocalizes with neurons (NeuN). AIE rats also exhibit reversal learning deficits. | [23] |
| Human | AUD | Orbitofrontal Cortex | ↑ HMGB1 correlated with earlier age of drinking onset (IHC), also ↑ RAGE | [74] |
| Rat (Wistar) | AIE | Orbitofrontal Cortex | ↑ HMGB1 (IHC) and ↑RAGE | [74] |
| Rat (Sprague) | CE (7% liquid diet, 15 days), or CIE (7% liquid diet intermittent) | Cortex (whole brain) | ↑ HMGB1 (mRNA) during CE and CIE withdrawal but not intoxication; also increased TLR4 (mRNA) but no change in MyD88 (mRNA) or NFĸB (mRNA) a ↑ HMGB1 (mRNA) during CE and CIE withdrawal blocked by CRF1 antagonist (CP154,526: 10 mg/kg) and ethyl pyruvate (75 mg/kg) but not the HMGB1 antagonist glycyrrhizin | [78] |
| Human | AUD | Orbitofrontal Cortex | ↑ HMGB1 correlates with TLR and age of drinking onset | [72] |
| Rat (Wistar) | 0 → 100 mM EtOH | hippocampal- entorhinal cortex organotypic slice culture | ↑ HMGB1 (mRNA), ↑ HMGB1 released into media (ELISA) | [72] |
| Rat (Wistar) | 0 → 100 mM EtOH | hippocampal- entorhinal cortex organotypic slice culture | Ethanol dose dependently ↑ HMGB1 (mRNA) and ↑ HMGB1 released into media (ELISA). Acetyl-HMGB1 is released; HDAC inhibitors also increase acetyl- HMGB1 release into media | [79] |
| Rat (Wistar) | AIE | Hippocampus | ↑ HMGB1 (mRNA) | [80] |
| Human | AUD | Hippocampus | ↑ HMGB1 (WB) ↑ HMGB1/1L-1β complexes (WB) | [81] |
| Mouse | Acute 6 g/kg i.g. | Whole brain Cortex Plasma Liver | ↑ HMGB1 (ELISA, IHC, WB) ↑ HMGB1/1L-1β complexes (Western blot, IHC) ↑ HMGB1 (ELISA) ↑ HMGB1 (WB) | [81] |
| Human | AUD | Hippocampus | ↑ HMGB1 in Human AUD Hippocampus (ELISA) | [82] |
| Rat | 25–100 mM ethanol (48 h) | hippocampal- entorhinal cortex organotypic slice culture | ↑ MV-HMGB1 (ELISA) and miRNA Let7 ↑ HMGB1/Let7 complexes in MV (ELISA) | [82] |
| Rat (Wistar) | AIE | Hippocampus | ↑ HMGB1, TLR4, TNFα, IkBα (mRNA) and loss of neurogenesis (DCX, IHC) a Prevented with concurrent voluntary exercise or indomethacin | [83] |
| Human (young adult) ♀ ♂ | Binge Drinkers | Serum | ↑ HMGB1 (ELISA) in female but not male subjects following acute binge alcohol | [84] |
| Rat (Wistar) | AIE | Hippocampus | ↑ HMGB1 (IHC), ↑ RAGE, ↑ TNFRSF25, cleaved caspase-3, pNFĸB-p65 a HMGB1 changes not reversed with donepezil; other proinflammatory markers reversed by donepezil | [85] |
| Mouse/Human cell line | 100 mM EtOH (24 h) | BV2, SH-SY5Y BV2+ SH-SY5Y co-culture | 24 h EtOH did not impact HMGB1 (mRNA) in BV2, SH-SY5Y or co-culture 24 h EtOH ↑HMGB1 release into media in BV2 and SH-SY5Y cultures but not in co-cultured BV2+SH-SY5Y preps. IL-4 and IL13 mRNA increased in co-culture EtOH EtOH ↑ TLR4 (mRNA)in co-culture BV2/SH-SY5Y, but co-culture attenuated EtOH TLR3/TLR7 (mRNA) and iNOS (mRNA) | [86] |
| Human (AUD) | AUD | Orbitofrontal Cortex | AUD increases multiple TLR and NFĸB genes that correlate with increased expression of HMGB1 | [73] |
| Rat (Wistar) | AIE | Basal Forebrain | ↑ HMGB1 (IHC) with ↑TLR4, ↑ pNFĸB p65, and ↑ RAGE as well as ↑ H3K9me2 and decreased ChAT by AIE a Galantamine prevented/reversed AIE-induced changes in adulthood | [87] |
| Rat (Wistar) | AIE | Dentate gyrus of the hippocampus | ↑ HMGB1 (IHC) and other proinflammatory markers including CCL2, COX2 and cleaved Caspase-3 while decreasing neurogenesis (DCX) a galantamine prevented/reversed | [88] |
| Human ♀ ♂ | AUD, ALD | Serum | ↑ HMGB1 in ALD relative to AUD (ELISA); predicts mortality in AUD. | [89] |
| Rat (Wistar) | In vivo: AIE Ex vivo: dsHMGB1 and rHMGB1, 100 mM EtOH for 4 days | In vivo: Basal Forebrain Ex vivo: BFCN organotypic slice culture | In vivo: ↑ HMGB1 (mRNA) Ex vivo: dsHMGB1 and rHMGB1 both reduce ChAT. Ethanol releases HMGB1 into media. REST and G9a induction lead to ChAT gene silencing. Loss of ChAT blocked by HMGB1 antagonist glycyrrhizin | [90] |
| Rat (Wistar) ♀ ♂ | AIE | Dentate gyrus of the hippocampus | ↑ HMGB1 (IHC) a Indomethacin reversed AIE-induced loss of neurogenesis and cholinergic markers and reduced HMGB1 (IHC) | [91] |
| Other HMGB1-RELATED primary literature | ||||
|---|---|---|---|---|
| Species | Exposure | Assessment | Results | References |
| Rat (unspecified) | 0–5 mM Glutamate; 0–100 µM NMDA | hippocampal- entorhinal cortex organotypic slice culture | Glutamate dose-dependently ↑ HMGB1 release into media parallel to ↑ cell death (exclusion dye propidium iodide). NMDA similarly dose-dependently ↑ HMGB1 release into media parallel to ↑ cell death (exclusion dye propidium iodide). | [92] |
| Vglut2-Cre/ChR2-eYFP mice | ChR2 stimulated | In vivo: DRG Ex vivo: DRG neuronal culture | ↑ HMGB1 cytoplasmic translocation (IHC) ↑ HMGB1 release (WB/ELISA) | [93] |
| Syn-Cre/HMGB1fl/flMice | Neuronal HMGB1 ablation | DRG | Neuronal HMGB1 ablation reduced hyperalgesia following sciatic nerve injury and attenuated proinflammatory cytokine and chemokine responses (ELISA: TNFα, CXCL1, IL18) | [93] |
| Rat (Wistar) | In vivo: LPS (1 mg/kg, i.p.); Ex vivo: LPS (100 ng/mL), dsHMGB1 | Basal forebrain (in vivo); BFCN organotypic slice culture (ex vivo) | dsHMGB1 and LPS trigger TLR4 induction of REST and G9a gene silencing to cholinergic transcriptome. | [94] |
| CD-1 mice | Radioactive labeled HMGB1 | Whole brain Serum | HMGB1 is transported across the BBB in both directions. LPS exposure ↑HMGB1 transport in part by disrupting the BBB and in part through a transport mechanism. | [95] |
| Swiss albino or transgenic Thy1-ChR2- YFP and hGFAP-GFP adult mice | optogenetic stimulation or pinprick for cortical spreading depolarization | Cortex | ↑ HMGB1 nuclear translocation (IHC) and ↑ HMGB1 extracellular vesicles with some indication of astrocyte-HMGB1 but not microglial-HMGB1 interactions | [96] |
| HMGB1-Related review articles | |
|---|---|
| Findings | Reference |
| This review covers the rapid release of HMGB1 from neurons during a seizure, increasing astrocyte and microglial IL-1β/HMGB1 synthesis and release. Long lasting decreases in seizure threshold are linked to persistent increases in these signals. | [97] |
| Proposed the hypothesis that neuroimmune signaling contributes to the neurobiology of alcohol and substance use disorders. | [55] |
| The review covers evidence supporting drug induced increases in TLR in brain, particularly microglia, that respond to HMGB1 and microRNAs (miRNAs). Studies supporting ethanol enhanced TLR innate immune signaling changes gene transcription through epigenetic mech anisms alternating synapses and neuronal networks. Addiction involves progressive stages of drug binge intoxication and withdrawal that are linked to progressive increases in TLR signaling. | [71] |
| This review discusses HMGB1 oxidation-reduction and changes activities through multiple cell surface receptors. Also, this review discusses recent discoveries indicating that HMGB1 released from neurons mediates inflammation via the TLR4 receptor system. | [98] |
| The studies reviewed support roles for neuroimmune signaling as well as epigenetic reprogramming of neurons and glia, which create a vulnerable neuro- environment. Some of these changes are reversible, giving hope for future treatments to prevent many of the long-term consequences of adolescent alcohol abuse. | [99] |
| AIE increases adult alcohol drinking, risky decision-making, reward-seeking, and anxiety as well as reducing executive function that increase risks for AUD. AIE causes persistent increases in adult brain neuroimmune signaling high-mobility group box 1 (HMGB1), TLR, RAGE and other innate immune genes. These genes are also increased in human AUD brain. HMGB1 release by ethanol, both free and within extracellular vesicles shifts transcription and cellular phenotype. For example, RE-1 silencing transcript blunts cholinergic gene expression, shifting neuronal phenotype. Inhibition of HMGB1 neuroimmune signaling, histone methylation enzymes, and galantamine, the cholinesterase inhibitor, both prevent and reverse AIE pathology. These findings provide new targets that may reverse AUD neuropathology as well as other brain diseases linked to neuroimmune signaling. | [1] |
| This is a review of HMGB1 immune cell functions including promoting DNA damage repair in the nucleus, sensing nucleic acids and inducing innate immune responses and autophagy and stimulating immunoreceptors. Signaling, cellular functions and clinical relevance of HMGB1 in various diseases are discussed. | [77] |
a
AIE, adolescent intermittent ethanol; AUD, alcohol use disorder; ALD, Alcohol-related Liver Disease; BBB, blood brain barrier; CCL2, c-c motif ligand 2; COX2, cyclooxygenase-2; DCX, doublecortin; DRG, dorsal root ganglion; dsHMGB1, disulfide high mobility group box 1; ELISA, enzyme-linked immunosorbent assay; EtOH, ethanol; IHC, immunohistochemistry; IL, infralimbic; NeuN, neuronal nuclear protein; LPS, lipopolysaccharide; MV, microvesicle; pNFĸB, phosphorylated nuclear factor kappa-light chain enhancer of activated B cells; PL, prelimbic; RAGE, receptor for advanced glycation end products; TNFRSF25, tumor necrosis factor receptor superfamily 25; WB, western blot.