Suppression of the macrophage proteasome by ethanol impairs MHC class I antigen processing and presentation.

Alain J D'Souza,Xiaowen L Rudner,Michelle N Kelly,Judd E Shellito,Shyamal D Desai,Sanbao Ruan

doi:10.1371/journal.pone.0056890

Alain J D'Souza, Xiaowen L Rudner + Show 4 more

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https://doi.org/10.1371/journal.pone.0056890

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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.

Highlights

Alcohol abuse is a major health concern in the United States
We investigated the effects of acute ethanol exposure on the proteasome activity and peptide-processing machinery of murine peritoneal macrophages
We demonstrate that ethanol suppresses the proteasome function impairs peptide processing required for MHC Class I restricted antigen presentation in macrophages

Summary

Introduction

Alcohol abuse is a major health concern in the United States. Episodic excessive (acute) alcohol consumption or binge drinking accounts for 23% of the alcohol abusers in the United States [1]. Binge drinking alters and suppresses cellular functions of both the innate and adaptive arms of the immune system including macrophage functions such as phagocytosis, cytokine and chemokine release, and antigen presentation [4,5,6]. By efficiently processing and presenting self and non-self-proteins to T-lymphocytes these APC’s orchestrate an efficient immune response within the host. The ability of these cells to effectively process foreign antigens for presentation is crucial in determining how rapidly the adaptive immune system responds and, in concert with innate immunity, efficiently mounts an immune response [7,8]

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