Inflammasome-Mediated Inflammation in Liver Ischemia-Reperfusion Injury

Abstract

Ischemia-reperfusion injury is an important cause of liver damage occurring during surgical procedures including hepatic resection and liver transplantation, and represents the main underlying cause of graft dysfunction and liver failure post-transplantation. To date, ischemia-reperfusion injury is an unsolved problem in clinical practice. In this context, inflammasome activation, recently described during ischemia-reperfusion injury, might be a potential therapeutic target to mitigate the clinical problems associated with liver transplantation and hepatic resections. The present review aims to summarize the current knowledge in inflammasome-mediated inflammation, describing the experimental models used to understand the molecular mechanisms of inflammasome in liver ischemia-reperfusion injury. In addition, a clear distinction between steatotic and non-steatotic livers and between warm and cold ischemia-reperfusion injury will be discussed. Finally, the most updated therapeutic strategies, as well as some of the scientific controversies in the field will be described. Such information may be useful to guide the design of better experimental models, as well as the effective therapeutic strategies in liver surgery and transplantation that can succeed in achieving its clinical application.

Keywords: inflammasome; ischemia-reperfusion injury; liver; partial hepatectomy; steatosis; transplantation.

Figure 1

Schematic representation of the inflammasome activation pathways. Firstly, expression of inflammasome components is activated. Secondly, signaling by DAMPs and PAMPs results in the inflammasome activation, which entails pro-caspase-1 activation and cleavage of pro-IL-1β and pro-IL-18 into their mature forms. Abbreviations: AIM2, absent in melanoma 2; ASC, Apoptosis-associated speck-like protein containing a caspase recruitment domain (CARD); ATP, Adenosine triphosphate; DAMP, damage-associated molecular pattern; IL, Interleukin; IL-1R, Interleukin-1 receptor; NFκB, nuclear factor kappa B; NLRC4, NLR family CARD domain-containing protein 4; NLRP3, NLR pyrin domain containing protein 3; PAMP, pathogen-associated molecular pattern; ROS, reactive oxygen species; T3SS, type III secretion system; TLR, Toll-like receptor; TNF, Tumor necrosis factor.

Figure 2

Schematic representation of the role of inflammasome in different experimental models of warm I/R injury. (A) Experimental models of 30 (A.1), 60 (A.2) and 90 (A.3) minutes of warm ischemia-reperfusion injury without hepatic resection. (B) Experimental models of partial hepatectomy without ischemia-reperfusion. (C) Experimental models of partial hepatectomy with 45 min of warm ischemia-reperfusion injury. Abbreviations: AKT, Protein kinase B; AP-1, Activator protein 1; ASC, Apoptosis-associated speck-like protein containing a CARD; BHB, β-hydroxybutyric acid; Cat B, Cathepsin B; Dex, Dexmedetomidine; DHA, Docosahexaenoic acid; FOXO1, Forkhead box protein O1; HMGB1, High mobility group box 1; HO-1, Heme oxygenase 1; HSF1, Heat shock transcription factor 1; IL, Interleukin; NF-κB, Nuclear factor kappa-light-chain-enhancer of activated B cells; NLRC4, NLR family CARD domain-containing protein 4; NLRP3, NLR pyrin domain containing protein 3; Nrf2, Nuclear factor erythroid 2-related factor 2; Panx1 Inh, Pannexin-1 inhibitor; RAP1, Repressor activator protein 1; STAT3, Signal transducer and activator of transcription 3; T3, 3,3’,5-triiodothyronine; TLR4, Toll-like receptor 4; TNF, Tumor necrosis factor; XBJ, Xuebijing; XBP1, X-box-binding protein 1.

Figure 3

Schematic representation of the role of inflammasome in different experimental models of cold I/R injury. (A) ex vivo liver transplantation model. (B) in vivo liver transplantation from non-cadaverid donors (B.1) and from cardiac-circulatory death donors (B.2) models. Abbreviations: AKT, Protein kinase B; ASC, Apoptosis-associated speck-like protein containing a CARD; DCD, Cardiac-circulatory death; HOPE, Hypothermic oxygenated perfusion; HMP, Hypothermic machine perfusion; IL, Interleukin; IL-1RA, IL-1R antagonist; LT, liver transplantation; NF-κB, Nuclear factor kappa-light-chain-enhancer of activated B cells; NLRP3, NLR pyrin domain containing protein 3; PI3K, Phosphoinositide 3-kinase; PTEN, Phosphatase and tensin homolog; TXNIP, Thioredoxin-interacting protein; TLR4, Toll-like receptor 4.