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.
Highlights
The nucleotide-binding and oligomerization domain (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
Toll-like receptors (TLRs) are to recognize both damage-associated molecular patterns (DAMPs) that derive from endogenous cells under stress or undergoing death processes as well as pathogenassociated molecular patterns (PAMPs) that are characteristic of microbial invaders
TLR sensing of DAMPs and PAMPs inevitably results in downstream signaling that leads to the nuclear translocation of the transcription factor NF-κB, which directly regulates the expression of NLRP3 and pro-IL-1β, neither of which is expressed in resting macrophages at significant levels [18,19]
Summary
NLRP3 is a three-domain protein containing an N-terminal pyrin domain, a central nucleotide-binding and oligomerization domain (NOD), and a C-terminal leucine-rich repeat domain [1,2]. The activation signal follows the priming signal, and is transduced by numerous mechanisms including alterations in ionic flux, mitochondrial DNA release, reactive oxygen species, and lysosomal damage and dysfunction. These pathways are elegantly reviewed in [1], and of particular interest to the field of organ transplant are the connections between. Exposure to poreforming 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. The activation of TLRs stimulates the formation of RIP1–FADD-caspase-8 complex accelerating NF-kB transcription
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