NLRP3 inflammasome ‘off switch’ reverses effects of chronic inflammation
Research into age-related chronic inflammatory disorders has identified an ‘off switch’ on the NLRP3 inflammasome that could be targeted in new therapies.
Researchers have identified that deacetylation of a section of the NLRP3 inflammasome acts as an ‘off switch’ for inflammation. The team suggest that therapeutics targeting this switch could be used to improve or reverse a range of ageing-related disorders exacerbated by chronic inflammation, including multiple sclerosis (MS), Alzheimer’s, Parkinson’s, diabetes and cancers.
“My lab is very interested in understanding the reversibility of ageing,” said senior author Danica Chen, associate professor of metabolic biology, nutritional sciences and toxicology at University of California (UC), Berkeley, US. “In the past, we showed that aged stem cells can be rejuvenated. Now, we are asking: to what extent can ageing be reversed? And we are doing that by looking at physiological conditions, like inflammation and insulin resistance, that have been associated with ageing-related degeneration and diseases.”
The study showed that the overactivation of the NLRP3 inflammasome seen in chronic inflammation can be turned off by deacetylation of a certain residue.
Chen explained: “This acetylation can serve as a switch. So, when it is acetylated, this inflammasome is on. When it is deacetylated, the inflammasome is off.”
In mice the team discovered that a protein, SIRT2, was responsible for deacetylating the NLRP3 inflammasome. When SIRT2 was knocked-out by the researchers, the mice had increased inflammation and higher insulin resistance by age two than their normal counterparts.
In older mice the team destroyed the immune system with radiation and then rebuilt it with stem cells, which either produced acetylated or deacetylated inflammasomes. Within six weeks the deacetylated NLRP3 inflammasome recipients had lowered insulin resistance; therefore, the researchers concluded that deacetylating the NLRP3 inflammasome could be a treatment for metabolic disease.
“I think this finding has very important implications in treating major human chronic diseases,” Chen said. “It’s also a timely question to ask, because in the past year, many promising Alzheimer’s disease trials ended in failure. One possible explanation is that treatment starts too late, and it has gone to the point of no return. So, I think it’s more urgent than ever to understand the reversibility of ageing-related conditions and use that knowledge to aid drug development for ageing-related diseases.”
The study was published in Cell Metabolism.