In a new study from University of California San Diego, researchers discover a signaling pathway that activates the NLRP3 inflammasome implicated in several severe chronic inflammatory disorders.
They found that drugs that turn off the NLRP3 inflammasome could be very useful for treating a variety of inflammatory disorders, from osteoarthritis to Alzheimer’s disease and cancer.
Inflammation is part of the body’s natural healing process.
But when it becomes chronic, inflammation can lead to cancer, Alzheimer’s disease and other conditions.
Inflammasomes are protein-based molecular machines. They can trigger inflammation in response to different signals generated by cell stress, tissue injury or infectious organisms.
For example, Interleukin 1β (IL-1β) is an inflammatory cytokine or hormone responsible for beneficial and adverse effects of inflammation.
Normally, IL-1β is produced in very low amounts, but in response to injury, environmental stress, infection or chronic inflammation, production of IL-1β is highly increased.
Production and secretion of IL-1β is regulated by inflammasomes.
In addition to an enzyme called caspase-1, inflammasomes contain sensor proteins that respond to different signals generated by cell stress, tissue injury or infectious organisms.
One of the most important and versatile sensors is NLRP3, which is responsible for inflammasome activation and IL-1β production in response to tissue injury or different microparticles, including asbestos and silica dust.
NLRP3 activators include microcrystals of cholesterol or uric acid, which trigger the inflammation associated with atherosclerosis or gout, respectively.
But until now, it was not clearly understood how environmental stress and tissue injury activate the NLRP3 inflammasome.
Without such knowledge, it was impossible to rationally design specific inhibitors of the NLRP3 inflammasome.
In the study, the researchers examined the critical role that the enzyme cytosine monophosphate kinase 2 (CMPK2) plays in the activation of NLRP3 and IL-1β production and subsequently in chronic inflammatory disorders.
CMPK2 belongs to a family of enzymes called nucleotide kinases, some of whose members have already been successfully targeted by the pharmaceutical industry.
According to the team, in gout and osteoarthritis CMPK2 inhibitors might reduce inflammation, pain and tissue damage.
In Alzheimer’s and Parkinson’s, they may slow progression and loss of cognitive function.
A recent study showed that administering an antibody targeting IL-1β reduces the likelihood of a second cardiac infarction in patients who already have undergone one heart attack.
Further analysis of the data found that it had an even greater positive effect in patients with lung cancer.
The team predicts that specific inhibitors of CMPK2 can be easily and rapidly developed.
And once available, such compounds may provide people with new treatments for many diverse untreatable and common illnesses, including osteoarthritis, Alzheimer’s disease and lung cancer.
Zhenyu Zhong, Ph.D., is the first author and UC San Diego School of Medicine postdoctoral researcher.
Michael Karin, Ph.D., Distinguished Professor of Pharmacology and Pathology, is the senior author of the study.
The study is published in the journal Nature.
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Journal reference: Zhenyu Zhong et al, New mitochondrial DNA synthesis enables NLRP3 inflammasome activation, Nature (2018). DOI: 10.1038/s41586-018-0372-z.
