Hippocampal TNF-death receptors, caspase cell death cascades, and IL-8 in alcohol use disorder

Abstract

The relationship between increased neuroimmune gene expression and hippocampal degeneration in alcohol use disorder (AUD) and other mental diseases is poorly understood. We report here that tumor necrosis factor receptor superfamily death receptor 3 (TNFRSF25, DR3) and Fas receptors (Fas) that initiate caspase cell death cascades are increased in AUD hippocampus and following a rat adolescent binge drinking model. Death receptors are known inducers of apoptosis and cell death that recruit death domain (DD) proteins FADD and TRADD and caspases to form death-inducing signaling complexes (DISC). In postmortem human AUD hippocampus, mRNA and IHC protein are increased for the entire death receptor cascade. In AUD hippocampus, ligand-death receptor pairs, i.e., TL1A-DR3 and FasL-Fas, were increased, as well as FADD and TRADD, and active caspase-8,-7,-9, and caspase-3. Further, pNFκB p65, a key neuroimmune transcription factor, and IL-8, a chemokine, were significantly increased. Interestingly, across AUD patients, increases in DR3 and Fas correlated with TRADD, and TRADD with active caspase+IR and IL-8+IR, consistent with coordinated activation of neuronal DISC mediated death cascades and neuroimmune gene induction in AUD. These findings support a role for DR3 and Fas neuroimmune signaling in AUD hippocampal neurodegeneration.

Comparative gene pathway analysis during adolescent binge-EtOH exposure, withdrawal, and following abstinence

“…The TNFRSF gene family itself is involved in the regulation of neuroinflammation and induction of apoptosis through the activation of caspase 8 (Wang et al, 2008) while RIPK1, a gene that encodes a member of the receptor-interacting protein (RIP) family of serine/threonine protein kinases, is involved in regulating neuroinflammation and cell death through apoptotic and necrotopic pathways (Lalaoui et al, 2020; Weinlich & Green, 2014). Together these data suggest that the protracted upregulation of neuroinflammatory genes could contribute to the presence of chronic neuroinflammation and induction of astrocyte reactivity that has previously been described in a rat model of adolescent binge drinking (Liu et al, 2020; Risher et al, 2015b).…”

TRAIL Mediates Neuronal Death in AUD: A Link between Neuroinflammation and Neurodegeneration

“…Since TLR7-induced neuronal death involves caspase-3 activation, we investigated if apoptotic death receptor signaling is involved. TLR7 activation in peripheral plasmacytoid dendritic cells induces expression of the death receptor ligand TRAIL/TNFSF10 and apoptosis [ 30 ], and we recently reported induction of TRAIL-associated death-inducing signaling complex (DISC) mediators in the human AUD hippocampus [ 20 ]. Therefore, we hypothesized that neuronal death due to TLR7 would involve TRAIL signaling.…”

“…However, recent work suggests that apoptotic mechanisms also contribute. We recently reported an increase in apoptotic death receptor (DR) signaling machinery in postmortem human AUD brain [ 20 ]. This included increases in DR adapter molecules such as fas-associated protein with death domain (FADD) and tumor necrosis factor receptor type 1-associated death domain protein (TRADD) as well as downstream caspases in human postmortem AUD brain [ 20 ].…”

“…We recently reported an increase in apoptotic death receptor (DR) signaling machinery in postmortem human AUD brain [ 20 ]. This included increases in DR adapter molecules such as fas-associated protein with death domain (FADD) and tumor necrosis factor receptor type 1-associated death domain protein (TRADD) as well as downstream caspases in human postmortem AUD brain [ 20 ]. Regulators of these extrinsic cell death cascade mediators are also altered in Alzheimer’s [ 21 ] and Parkinson’s [ 22 ] diseases.…”

Analysis of therapeutic potential of preclinical models based on DR3/TL1A pathway modulation (Review)

“…As a type I transmembrane protein with a calculated molecular weight of 45 kDa and 417-amino acid (aa) sequence, full-length DR3 is composed of an N-terminal signal sequence (aa 1-24), a repeat sequence consisting of four cysteine residues, two potential N -linked glycosylation sites (aa 25-198), a transmembrane domain (aa 199-244), and an intracellular domain with a DD (aa 255-417) ( 14 , 15 ). Notably, DR3 is exclusively expressed in lymphocyte-rich tissues, including the thymus, spleen, colon and intestine ( 11 ); however, low levels of expression are detected in the fetal lung ( 16 ), kidney ( 17 ), hippocampus ( 18 ) and peritoneal tissue ( 12 ). At the cellular level, DR3 is mainly expressed in immune cells, including naïve or resting CD4 + T cells, CD8 + T cells, natural killer T cells, innate lymphoid cells (ILCs), B cells and mononuclear cells ( 10 , 19 ).…”