Tumour Necrosis Factor in Neuroplasticity, Neurogenesis and Alcohol Use Disorder

Abstract

Alcohol use disorder is a pervasive and detrimental condition that involves changes in neuroplasticity and neurogenesis. Alcohol activates the neuroimmune system and alters the inflammatory status of the brain. Tumour necrosis factor (TNF) is a well characterised neuroimmune signal but its involvement in alcohol use disorder is unknown. In this review, we discuss the variable findings of TNF's effect on neuroplasticity and neurogenesis. Acute ethanol exposure reduces TNF release while chronic alcohol intake generally increases TNF levels. Evidence suggests TNF potentiates excitatory transmission, promotes anxiety during alcohol withdrawal and is involved in drug use in rodents. An association between craving for alcohol and TNF is apparent during withdrawal in humans. While anti-inflammatory therapies show efficacy in reversing neurogenic deficit after alcohol exposure, there is no evidence for TNF's essential involvement in alcohol's effect on neurogenesis. Overall, defining TNF's role in alcohol use disorder is complicated by poor understanding of its variable effects on synaptic transmission and neurogenesis. While TNF may be of relevance during withdrawal, the neuroimmune system likely acts through a larger group of inflammatory cytokines to alter neuroplasticity and neurogenesis. Understanding the individual relevance of TNF in alcohol use disorder awaits a more comprehensive understanding of TNF's effects within the brain.

Keywords: AUD; TNF; alcohol associated liver disease; alcohol use disorder; astrocytes; cytokines; excitotoxicity; microglia; neurogenesis; neuroinflammation; neuroplasticity; tumour necrosis factor; tumour necrosis factor-α; withdrawal.

Fig. 1

Overview of TNF signalling after alcohol consumption within a neuron. Peripheral immune cells release TNF following binding of lipopolysaccharide (LPS) through toll like receptor 4 (TLR4), which crosses the blood brain barrier (top left) to stimulate TNFR1 signalling and NF-κB translocation to the nucleus for transcription of TNF and other cytokines. High motility group box 1 (HMGB-1) also activates NF-κB through receptor for advanced glycation end products (RAGE) and toll like receptor 4 (TLR4). Microglia (blue), astrocytes (green), neurons (yellow) and oligodendrocytes (purple) are represented here with their respective TNF receptors.