Roles of the complement system in alcohol-induced liver disease

Abstract

Alcohol-induced liver disease (ALD) is a complex disorder, with a disease spectrum ranging from steatosis to steatohepatitis, cirrhosis, and hepatocellular carcinoma. Although the pathogenesis of ALD is incompletely understood and currently no effective drugs are available for ALD, several lines of evidence suggest that complement activation and oxidative stress play crucial roles in the pathogenesis of ALD. Complement activation can regulate the production of ROS and influence oxidative stress in ALD. Precise regulation of the complement system in ALD may be a rational and novel avenue to postpone and even reverse the progression of disease and simultaneously promote the repair of liver injury. In this mini-review, we briefly summarize the recent research progress, especially focusing on the role of complement and oxidative stress-induced transfer RNA-derived fragments, which might help us to better understand the pathogenesis of ALD and provide aid in the development of novel therapeutic strategies for ALD.

Keywords: Alcoholic; Complement system proteins; Liver Diseases; Molecular targeted therapy.

Figure 1.

Schematic overview of the complement cascade illustrating three activation pathways (classical, lectin, and alternative) and summarizing the biological effects of complement activation products. MAC, membrane attack complex.

Figure 2.

Schematic of CR2 site-targeted complement inhibitors. The CR2 moiety of the fusion protein binds the C3 degradation products iC3b, C3dg, and C3d that are covalently attached at sites of complement activation. Complement inhibitory constructs that have previously been prepared and characterized are CR2-Crry (murine inhibitor of C3 activation), CR2-CR1 (human inhibitor of C3 activation), CR2-fH (murine and human inhibitor of the alternative complement pathway), and CR2-CD59 (murine and human inhibitor of MAC formation). F1, factor 1; SP, serum protease; CR1/2, complement receptor 1/2; Crry, complement receptor-1 related protein y.

Figure 3.

Schematic graph showing that the complement system participates in the development of alcohol-induced liver disease. C3 convertase cleaves C3 to form C3a and C3b. ASP is the degraded product of C3a. C3b is an important component of C5 convertase. CR2-Crry is a site-targeted complement inhibitor that blocks all complement pathways at the C3 activation step. When anaphylatoxins C3a and C5a bind with their respective receptors, the TLR4/NF-κB pathway can be activated, resulting in the release of the inflammatory cytokine TNF-α, which participates in AFLD, either directly or indirectly, through the induction of insulin resistance. C3a and ASP bind to their receptor C5aR2 to promote the expression of Cyp2E1, which induces the production of ROS. The induced oxidative stress subsequently leads to the increased expression of Gly-tRF, which leads to AFLD via regulating the SIRT1 signaling pathway. The inflammatory response contributes to the development and progression of ALD. CR2, complement receptor 2; Crry, complement receptor 1-related protein y; ASP, acylation stimulating protein; Cyp2E1, cytochrome P450 family 2, subfamily E, polypeptide 1; GlytRFs, glycine tRNA-derived fragments; ROS, reactive oxygen species; TLR, toll-like receptor; TNF-α, tumor necrosis factor-alpha; AFLD, alcoholic fatty liver disease; ALD, alcohol-induced liver disease.