Suppression of the Macrophage Proteasome by Ethanol Impairs MHC Class I Antigen Processing and Presentation

Abstract

Alcohol binge-drinking (acute ethanol consumption) is immunosuppressive and alters both the innate and adaptive arms of the immune system. Antigen presentation by macrophages (and other antigen presenting cells) represents an important function of the innate immune system that, in part, determines the outcome of the host immune response. Ethanol has been shown to suppress antigen presentation in antigen presenting cells though mechanisms of this impairment are not well understood. The constitutive and immunoproteasomes are important components of the cellular proteolytic machinery responsible for the initial steps critical to the generation of MHC Class I peptides for antigen presentation. In this study, we used an in-vitro cell culture model of acute alcohol exposure to study the effect of ethanol on the proteasome function in RAW 264.7 cells. Additionally, primary murine peritoneal macrophages obtained by peritoneal lavage from C57BL/6 mice were used to confirm our cell culture findings. We demonstrate that ethanol impairs proteasome function in peritoneal macrophages through suppression of chymotrypsin-like (Cht-L) proteasome activity as well as composition of the immunoproteasome subunit LMP7. Using primary murine peritoneal macrophages, we have further demonstrated that, ethanol-induced impairment of the proteasome function suppresses processing of antigenic proteins and peptides by the macrophage and in turn suppresses the presentation of these antigens to cells of adaptive immunity. The results of this study provide an important mechanism to explain the immunosuppressive effects of acute ethanol exposure.

Binge alcohol promotes hypoxic liver injury through a CYP2E1–HIF-1α-dependent apoptosis pathway in mice and humans

“…For instance, various subunits of the 26S proteasomal complex can be covalently modified: 1) adduct formation with 4-hydroxynonenal [43]; 2) phosphorylation [44]; and 3) oxidative modification of Cys residues [45] in a CYP2E1-dependent manner, since proteasomal activities were not significantly decreased in alcohol-exposed Cyp2e1 -null mice [46]. In addition to the suppression by chronic alcohol administration, proteasomal activities can be also suppressed by acute binge alcohol exposure [47]. These types of modifications of the proteasomal subunits likely result in suppressed proteasomal activity, thus leading to increased HIF-1α levels.…”

Pathogenesis of alcoholic liver disease: Role of oxidative metabolism

“…Chronic alcohol ingestion can interfere with antigen presentation that is required to activate T and B cells and can impair dendritic cell differentiation [175][176][177][178] . Patients with AH have increased levels of circulating antibodies against modified protein adducts with HER and lipid-peroxidation-derived aldehydes, justifying the activation of the adaptive immune response [179,180] . HER and MDA antibodies have been detected in chronically ethanol-fed rats as well as in alcohol abusers, and they are associated with detection of peripheral blood CD4 + T cells that are responsive to these adducts.…”

[P4–449]: The Alzheimer's Disease‐associated R47h Variant of Trem2 Has an Altered Glycosylation Pattern and Protein Stability

“…We next treated cells with MG132, a proteasomal inhibitor, to block proteasomal degradation. TREM2 R47H was more elevated after MG132 treatment compared to wild-type (Figure 4B), indicating that this variant is unstable and degraded via the ER associated degradation (ERAD) pathway (Kroeger et al, 2009;D'Souza et al, 2013). We also treated cells with bafilomycin A1, a vATPase inhibitor, to block lysosomal degradation (Cho et al, The intensity of each band was measured using Image J and relative intensities are plotted.…”