The NLRP3 Inflammasome: Relevance in Solid Organ Transplantation

Abstract

The NOD, LRR, and pyrin domain-containing 3 (NLRP3) protein has been established as a central component of the inflammasome and regulates the inflammatory response to a myriad of environmental, microbial, and endogenous danger stimuli. Assembly of the NLRP3 inflammasome results in the cleavage and activation of caspase-1, in turn causing release of the pro-inflammatory interleukins 1-beta and 18. This activation response, while crucial to coordinated innate immune defense, can be aberrantly activated by the likes of cell-free DNA, and cause significant autoimmune pathology. Complications of autoimmunity induced by aberrant NLRP3 inflammasome activation have a great degree of mechanistic crossover with alloimmune injury in solid organ transplant, and stratagems to neutralize NLRP3 inflammasome activation may prove beneficial in solid organ transplant management. This article reviews NLRP3 inflammasome biology and the pathology associated with its hyperactivation, as well as the connections between NLRP3 inflammasome activation and allograft homeostasis.

Keywords: NLRP3; alloimmune injury; autoimmunity; donor-derived cell-free DNA; fibrosis; inflammasome; neutrophil extracellular trap; solid organ transplant.

Figure 1

NLRP3 inflammasome signaling in transplantation. This diagram displays the molecular mechanisms underlying NLRP3 inflammasome activation, with an emphasis on those specific to solid organ transplant. Classical Canonical NLRP3/caspase-1 activation: P2X7 receptor activation by extracellular ATP leads to MLKL activation. Exposure to pore-forming gasdermin D combined with lysosomal damage and cathepsin release promote potassium efflux, with consequent release of oxidized mitochondrial DNA and dd-cfDNA—leading to increase in mitochondrial ROS and cardiolipin externalization. This in turn promotes NLRP3 inflammasome oligomerization and activation with the consequent release of IL-1β,IL-18, and HMGB1 and the autocatalytic cleavage of caspase-1. This active form of caspase-1 is also a major driver of the cell death pathway pyroptosis (see main text). Non-canonical caspase-11-dependent NLRP3 activation—bacterial infection in transplant: Gram-negative bacteria activate caspase-11, cleaving pore-forming gasdermin D between the N-terminal and C-terminal domains. Cleaved gasdermin D promotes pyroptosis and the activation of canonical NLRP3-ASC-caspase-1 signaling. Non-canonical caspase-8 NLRP3 activation—fungal infection in transplant: TLRs activation by PAMPs and/or DAMPs such as dd-cfDNA activate the RIP1–FADD-caspase-8 pathway and NF-kB alongside the promotion of canonical NLRP3 activation. Moreover, fungal PAMPS, via dectin-1 activation, promote the activation of the MALT1–caspase-8–ASC complex, which promotes the processing and release of IL-1β. NLRP3 transcription steps: Transcription steps are regulated by TLRs—MyD88, TNFR and/or IFNα, β-JAK/STAT, which, promoting NF-κB activation, induce the transcription of pro-IL-1β, NLRP3, procaspase-1, IRF-3 and IRF-7, and procaspase-11. The activation of TLRs stimulates the formation of RIP1–FADD-caspase-8 complex accelerating NF-kB transcription.