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 inflammation marking MS has been linked to NLRP3 inflammasome activation.

The study, An Acetylation Switch of the NLRP3 Inflammasome Regulates Aging-Associated Chronic Inflammation and Insulin Resistance, was published in the journal Cell Metabolism.

Chronic inflammation, which results from an overactive immune response, can intensify with age and lead to a variety of illnesses, fromAlzheimersand MS to cancer and diabetes.

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.

Using models of older mice, the scientists 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 studys 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 proinflammatory 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 its 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.

Ana is a molecular biologist with a passion for discovery and communication. As a science writer, she looks for connecting the public, in particular patients and healthcare providers, with clear and quality information about the latest medical advances. Ana holds a Ph.D. in Biomedical Sciences from the University of Lisbon, Portugal, where she specialized in infectious diseases, epigenetics, and gene expression.

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Patrcia holds her PhD in Medical Microbiology and Infectious Diseases from the Leiden University Medical Center in Leiden, The Netherlands. She has studied Applied Biology at Universidade do Minho and was a postdoctoral research fellow at Instituto de Medicina Molecular in Lisbon, Portugal. Her work has been focused on molecular genetic traits of infectious agents such as viruses and parasites.

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