Emerging Role of NLRP3 Inflammasome and Pyroptosis in Liver Transplantation

Abstract

The nucleotide-binding domain leucine-rich repeat-receptor, pyrin domain-containing-3 (NLRP3) inflammasome contributes to the inflammatory response by activating caspase-1, which in turn participates in the maturation of interleukin (IL)-1β and IL-18, which are mainly secreted via pyroptosis. Pyroptosis is a lytic type of cell death that is controlled by caspase-1 processing gasdermin D. The amino-terminal fragment of gasdermin D inserts into the plasma membrane, creating stable pores and enabling the release of several proinflammatory factors. The activation of NLRP3 inflammasome and pyroptosis has been involved in the progression of liver fibrosis and its end-stage cirrhosis, which is among the main etiologies for liver transplantation (LT). Moreover, the NLRP3 inflammasome is involved in ischemia-reperfusion injury and early inflammation and rejection after LT. In this review, we summarize the recent literature addressing the role of the NLRP3 inflammasome and pyroptosis in all stages involved in LT and argue the potential targeting of this pathway as a future therapeutic strategy to improve LT outcomes. Likewise, we also discuss the impact of graft quality influenced by donation after circulatory death and the expected role of machine perfusion technology to modify the injury response related to inflammasome activation.

Keywords: NLRP3 inflammasome; graft rejection; ischemia-reperfusion injury; liver transplantation; pyroptosis.

Figure 1

NLRP3 inflammasome and pyroptosis activation during liver inflammation. In the first step of the canonical NLRP3 inflammasome activation, PAMPs and DAMPs stimulate TLR receptors and the translocation of NF-κB to the cell nucleus, which, in turn, increases the transcription of the inflammasome components and expression of pro-IL-1β and pro-IL-18. A second signal, such as P2X7R activation via ATP or crystalline structures, induces the formation of active NLRP3 oligomers leading to the activation of caspase-1. Caspase-1 cleaves the N- terminus of gasdermin D and converts pro-IL-1β and pro-IL-18 into mature IL-1β and IL-18. NLRP3 inflammasome and gasdermin D must be in oxidized form to be active, highlighting the important role of ROS in the regulation of this pathway. Pyroptosis occurs by the insertion of the cleaved gasdermin D N-terminal fragment into the plasma membrane, creating oligomeric pores and allowing the release of proinflammatory mediators such as IL-1β and IL-18 to the extracellular space. Gasdermin D pores also induce cell lysis which further induces inflammation by releasing additional inflammatory intracellular products.

Figure 2

Activation of inflammasome/pyroptosis pathway in liver diseases. Activation of inflammasome in hepatocytes and KCs in early stages of inflammation associated to several liver diseases such as ALD, NAFLD or virus infection induce the release of a plethora of pro-inflammatory compounds, which will active HSCs and evoke an state of fibrosis which can degenerate to the end stage cirrhosis. This process can lead to liver transplantation as ultimate solution.

Figure 3

Inflammasome activation during LT. During transplantation surgery, liver IRI increases the rate of acute and chronic rejection and is estimated to be responsible for 10% of early organ failure. DCD has been increasing in recent years, attempting to alleviate the deficit in the number of available organs for transplantation. However, warm ischemia associated with the super-rapid recovery of DCD organs is related to higher NLRP3 activation compared with DBD donors. In this regard, the introduction of the NRP technique has reduced ischemic damage from DCD. Moreover, NRP could be used as the first line of inflammasome inhibitor drug delivery already in the donor. During cold ischemia storage, multiple ROS and DAMPs are released from damaged cells, and these molecules activate the NLRP3 inflammasome and ultimately pyroptosis during reperfusion, which have an impact in the inflammatory response during the early stage of acute rejection in liver transplantation. Recently, the introduction of the extracorporeal machine perfusion technique, HMP and NMP, has improved the liver transplant outcome by NLRP3 inflammasome inhibition during I/R. Furthermore, MP appears as a contrasted platform for the use of specific drugs or even siRNA delivery.