Inflammasome Pathway Linked to MS and Diseases of Aging Has an ‘Off’ Switch, Early Study Says
Immune cells have an inflammation ‘switch’ that involves the NLRP3 inflammasome pathway, and targeting it may prevent or even reverse the chronic inflammation seen in diseases like multiple sclerosis (MS) and in conditions associated with aging, an early study suggests.
The study, “An Acetylation Switch of the NLRP3 Inflammasome Regulates Aging-Associated Chronic Inflammation and Insulin Resistance,” was published in the journal Cell Metabolism.
The molecular triggers responsible for provoking the immune system, however, are not clear.
A team led by researchers at the University of California (UC), Berkeley, discovered a molecular “switch” that controls chronic inflammation in the body.
The scientists used mouse models of aging, and developed a cell-based system that models aging-associated inflammation. It simulates the effects of inflammation over metabolism — including for insulin resistance, a pre-diabetic condition marked by cells that no longer respond well to insulin.
“My lab is very interested in understanding the reversibility of aging,” Danica Chen, professor at UC Berkeley, and the study’s senior author, said in a news story.
“In the past, we showed that aged stem cells [progenitor cells with the potential to develop into several cell types] can be rejuvenated. Now, we are asking: to what extent can aging be reversed?
“And we are doing that by looking at physiological conditions, like inflammation and insulin resistance, that have been associated with aging-related degeneration and diseases,” Chen added.
Using their models, the team showed that a pathway wired to immune cells, called theNLRP3 inflammasome, is at the origin of aging-associated inflammation. Importantly, the researchers found a potential way to switch it off.
This inflammasome consists of a sensor molecule, called NLRP3, that senses threats or danger signals inside immune cells, to rapidly recruit other proteins and launch an inflammatory response. Such a pathway is central to coordinating pro‐inflammatory responses, and has been implicated in chronic conditions like MS, cancer, and diabetes.
Research in MS patients suggests that inflammasome activation occurs during disease. Experiments in MS mouse models also support the NLRP3 inflammasome as critical and necessary to MS development.
Working with mice and immune cells called macrophages, Chen and his colleagues discovered that a specific chemical modification called acetylation (the addition of an acetyl group to a compound) works as a molecular “switch” that turns on this inflammasome.
When NLRP3 is acetylated, it stays in a more active form that favors inflammation, they reported. However, this active state can be prevented by a protein called SIRT2 that takes out the acetyl (essentially, deacetylates NLRP3), shutting off the inflammasome.
Mice genetically engineered to lack SIRT2 showed more signs of inflammation at an older age than did their normal counterparts. These mice also exhibited higher insulin resistance, a condition associated with type 2 diabetes and metabolic syndrome.
“This acetylation can serve as a switch,” Chen said. “So, when it is acetylated, this inflammasome is on. When it is deacetylated, the inflammasome is off.”
This finding suggests that treatments that deacetylate — switch off — the NLRP3 inflammasome might help to prevent or treat conditions related to aging and inflammation, and perhaps age-related degeneration in general.
Studying older mice that produced either the deacetylated or the acetylated version of NLRP3, the team saw that those with the deacetylated, or “off,” version of the inflammasome had better insulin resistance after six weeks.
This suggests that targeting NLRP3 acetylation might actually reverse inflammatory conditions.
“These results establish the dysregulation of the acetylation switch of the NLRP3 inflammasome as an origin of aging-associated chronic inflammation, and highlight the reversibility of aging-associated chronic inflammation and insulin resistance,” researchers wrote.
“I think this finding has very important implications in treating major human chronic diseases,” Chen said. “I think it’s more urgent than ever to understand the reversibility of aging-related conditions, and use that knowledge to aid a drug development for aging-related diseases.”