Redox signaling and the innate immune system in alcoholic liver disease

Abstract

The development of alcoholic liver disease (ALD) is a complex process involving both parenchymal and nonparenchymal cells resident in the liver. Although the mechanisms for ALD are not completely understood, it is clear that increased oxidative stress, and activation of the innate immune system are essential elements in the pathophysiology of ALD. Oxidative stress from ethanol exposure results from increased generation of reactive oxygen species and decreased hepatocellular antioxidant activity, including changes in the thioredoxin/peroxiredoxin family of proteins. Both cellular and circulating components of the innate immune system are activated by exposure to ethanol. For example, ethanol exposure enhances toll-like receptor-4 (TLR-4)-dependent cytokine expression by Kupffer cells, likely due, at least in part, to dysregulation of redox signaling. Similarly, complement activation in response to ethanol leads to increased production of the anaphylatoxins, C3a and C5a, and activation C3a receptor and C5a receptor. Complement activation thus contributes to increased inflammatory cytokine production and can influence redox signaling. Here we will review recent progress in understanding the interactions between oxidative stress and innate immunity in ALD. These data illustrate that ethanol-induced oxidative stress and activation of the innate immune system interact dynamically during ethanol exposure, exacerbating ethanol-induced liver injury.

FIG. 1.

The methionine cycle and taurine synthesis. THF, tetrahydrofolate; MS, methionine synthase; BHMT, betaine homocysteine methyltransferase; SAM, S-adenosyl methionine; SAH, S-adenosyl homocysteine.

FIG. 2.

Thioredoxin (Trx) is an endogenous protein with antioxidant and antiapoptotic properties. Trx scavenges and reduces reactive oxygen species via a family of proteins known as peroxiredoxins. Additionally, Trx reduces oxidized proteins. Once oxidized, Trx is reduced by the enzyme thioredoxin reductase (TrxR) and the hydrogen donor NADPH. Trx is upstream of apoptosis signal-regulating kinase-1 (ASK-1), a protein involved in apoptosis, and prevents activation, signaling, and induction of apoptosis.

FIG. 3.

Toll-like receptor-4 (TLR-4) signaling via MyD-88-dependent pathways. Chronic ethanol exposure increases lipopolysaccharide (LPS) in the circulation, and initiates a signaling cascade via TLR-4 on the surface of Kupffer cells. This signaling pathway activates mitogen-activated protein kinases (MAPKs), p38, c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinases 1 and 2 (ERK1/2), resulting in increased tumor necrosis factor (TNF)-α expression and stability.

FIG. 4.

Chronic ethanol-induced liver injury involves MyD-88-independent signaling pathways. TLR-4 mediating signaling via MyD-88-dependent and MyD88-independent/TRIF pathways is illustrated schematically.

FIG. 5.

Activation and functions of complement. Complement is activated via the classical, lectin, or alternative pathways, culminating in the proteolytic cleavage of C3. Functions of complement include opsinin activity against bacteria and apoptotic cells, stimulation of inflammatory cytokine and chemokine expression, and lysis of targeted bacteria or cells.

FIG. 6.

Complement contributes to ethanol-induced liver injury in mice. C3 and C5 contribute to ethanol-induced increases in hepatic triglycerides and circulating alanine aminotransferease, respectively; CD55/decay accelerating factor (DAF), a complement regulatory protein, acts as a brake against ethanol-induced inflammation and liver injury.