Treatments for chronic inflammatory diseases are one step closer as University of Queensland researchers discover a way to stop inflammation in its tracks.
Associate Professor Kate Schroder and Dr. Rebecca Coll from UQ’s Institute for Molecular Bioscience and Professor Avril Robertson from UQ’s School of Chemistry and Molecular Biosciences led the study, which will inform the design of new drugs to stop the formation of a protein complex, called the inflammasome, which drives inflammation.
Dr. Coll, who is now a Lecturer at the Wellcome-Wolfson Institute for Experimental Medicine at Queen’s University Belfast, said the inflammasome was important in protecting our bodies from infection, but is also a key driver of unhealthy inflammation.
“Inflammation helps our bodies heal following infection, but when the inflammasome is not switched off, inflammation becomes damaging.
“Uncontrolled inflammation results in chronic diseases, such as Parkinson’s disease, Alzheimer’s disease and respiratory diseases such as asthma,” she said.
Associate Professor Schroder said the team’s exciting discovery gave new insight into how to stop inflammation at the molecular level.
“We previously identified a small molecule, MCC950, that inhibits the inflammasome to block inflammation in disease but, until now, we did not understand how it worked,” she said.
“We discovered that MCC950 binds directly to the inflammasome and inactivates it, turning off inflammation.
“Now that we understand how a small molecule can inhibit the inflammasome, we are very excited about the potential of inflammasome inhibitors as anti-inflammatory drugs.
The inflammasome was described a decade ago as a large intracellular signaling platform that contains a cytosolic pattern recognition receptor, especially a nucleotide-binding oligomerization domain-like receptor (NLR) or an absent in melanoma 2 (AIM2)-like receptor.
Among NLR inflammasome complexes, the NLRP3 inflammasome has been the most widely characterized and is a crucial signaling node that controls the maturation of two proinflammatory interleukin (IL)-1 family cytokines: IL-1β and IL-18.1,2,3
Activation of the pattern recognition receptor NLRP3 leads to recruitment of the adapter apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC), resulting in the activation of pro-caspase-1 into its cleaved form.1
Caspase-1 is known as an inflammatory caspase that plays a role in the maturation of IL-1β and IL-18 into active cytokines and the initiation of pyroptosis by autocatalysis and activation.4
Activation of the NLRP3 inflammasome is thought be regulated at both the transcriptional and post-translational levels.
The first signal in inflammasome activation involves the priming signal, induced by the toll-like receptor (TLR)/nuclear factor (NF)-κB pathway, to upregulate the expression of NLRP3, the level of which is otherwise relatively low in numerous cell types.5,6
Signal 2 is transduced by various pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) to activate the functional NLRP3 inflammasome by initiating assembly of a multi-protein complex consisting of NLRP3, the adaptor protein ASC, and pro-caspase-1.
Several molecular mechanisms have been suggested for NLRP3 activation to induce caspase-1 activation and IL-1β maturation.
These include pore formation and potassium (K+) efflux,7,8 lysosomal destabilization and rupture,9,10 and mitochondrial reactive oxygen species (ROS) generation.10,11,12
Evidence supports that the aberrant activation of the NLRP3 inflammasome is associated with the pathogenesis of various autoinflammatory, autoimmune, and chronic inflammatory and metabolic diseases, including gout, atherosclerosis, and type 2 diabetes.13,14,15
Thus, activation of the NLRP3 inflammasome should be tightly regulated to prevent unwanted host damage and excessive inflammation.
To date, several regulatory mechanisms and binding partners have been described in NLRP3 inflammasome activation. In this review, we focus on the molecular mechanisms that activate and regulate excessive NLRP3 inflammasome activation.
Both signal 1 and signal 2 are required for NLRP3 inflammasome activation. Activation of the NLRP3 inflammasome requires at least two signals: signal 1, also known as the priming signal, is mediated by microbial ligands recognized by TLRs or cytokines such as TNF-α. Signal 1 activates the NF-κB pathway, leading to upregulation of pro-IL-1β and NLRP3 protein levels. The signal 2 is mediated by numerous PAMP or DAMP stimulation, and promotes the assembly of ASC and pro-caspase-1, leading to activation of the NLRP3 inflammasome complex. Under noninfectious conditions, extracellular ATP and K+ efflux leads to the activation of NLRP3 inflammasome via the P2X7 receptor and pannexin-1. Various endogenous and exogenous particulates, including MSU crystals, CPPD crystals, cholesterol crystals, amyloid β, silica crystals, asbestos, and alum, promote lysosomal damage and release cathepsin B into the cytosol, leading to the NLRP3 inflammasome activation. Particulate matters (uric acid, silica, and alum) are also able to trigger inflammasome assembly through multiple purinergic receptor signaling. Additionally, calcium influx through TRPM2 activates NLRP3 inflammasome through mitochondrial ROS. Dissociated TXNIP, which is triggered by intracellular ROS, also activates the NLRP3 inflammasome. ADP, adenosine diphosphate; ATP, adenosine triphosphate; K+, potassium; ASC, apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain; CPPD, calcium pyrophosphate dehydrate; DAMPs, damage-associated molecular patterns; NLRP3, NACHT, LRR, and PYD domains-containing protein 3; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; P2X7, P2X purinoceptor 7; P2R, purinergic receptor; PAMPs, pathogen-associated molecular patterns; ROS, reactive oxygen species; TLRs, toll-like receptors; TNF-α, tumor necrosis factor-α TXNIP, thioredoxin (TRX)-interacting protein.
Professor Robertson said “UQ start-up Inflazome Ltd, which is developing targeted therapies for inflammatory diseases, had announced its plans to commence clinical trials of their inflammasome inhibitors in 2019, and other companies are competing in this space.
“We are keen to see results of these trials and hope that our discovery can lead to the efficient design of new molecules as anti-inflammatory drugs of the future,” she said.
The research was published in the scientific journal Nature Chemical Biology.
More information: MCC950 directly targets the NLRP3 ATPhydrolysis motif for inflammasome inhibition, Nature Chemical Biology (2019). DOI: 10.1038/s41589-019-0277-7 , https://www.nature.com/articles/s41589-019-0277-7
Journal information: Nature Chemical Biology
Provided by University of Queensland
