Identifying the molecular Switch for NLRP3 Inflammasome

Inflammation is an immunological double-edged sword. On one hand, the physiological changes that allow the body to mount an acute response to foreign substances, that if left unchecked could do great harm, have undoubtedly shaped the evolution of our species. Conversely, however, chronic inflammation, which results when old age, stress, or environmental toxins keep the body’s immune system in overdrive, can contribute to a variety of devastating diseases, from Alzheimer’s and Parkinson’s to diabetes and cancer.

In their current study, University of California Berkeley researchers led by Dr. Danica Chen, PhD, associate professor of metabolic biology, nutritional sciences, and toxicology showed that a bulky collection of immune proteins named NLRP3 inflammasome which is responsible for sensing potential threats to the body and launching an inflammation response can be essentially switched off by deacetylation. Their study is now published in Journal Cell Metabolism.

Interestingly, overactivation of the NLRP3 inflammasome has been linked to a variety of chronic conditions, including multiple sclerosis, cancer, diabetes, and dementia. Chen’s results suggest that drugs targeted toward deacetylating or switching off, this NLRP3 inflammasome might help prevent or treat these conditions and possibly age-related degeneration in general.

By studying mouse macrophages, the research team found that a protein called SIRT2 is responsible for deacetylating the NLRP3 inflammasome. Mice that were bred with a genetic mutation that prevented them from producing SIRT2 showed more signs of inflammation at the ripe old age of two than their normal counterparts. These mice also exhibited higher insulin resistance, a condition associated with type 2 diabetes and metabolic syndrome.

They showed that NLRP3 is modified by acetylation in macrophages and is deacetylated by SIRT2, an NAD+-dependent deacetylase and a metabolic sensor. The research team developed a cell-based system that models aging-associated inflammation, a defined co-culture system that simulates the effects of inflammatory milieu on insulin resistance in metabolic tissues during aging, and aging mouse models; and demonstrate that SIRT2 and NLRP3 deacetylation prevent, and can be targeted to reverse, aging-associated inflammation and insulin resistance.

The team also studied older mice whose immune systems had been destroyed with radiation and then reconstituted with blood stem cells that produced either the deacetylated or the acetylated version of the NLRP3 inflammasome. Those who were given the deacetylated, or “off,” version of the inflammasome had improved insulin resistance after six weeks, indicating that switching off this immune machinery might reverse the course of metabolic disease.

The findings of their study have very important implications in treating major human chronic diseases such as  Alzheimer’s disease and other aging-related diseases. This acetylation switch of the NLRP3 Inflammasome could lead to new ways to halt or even reverse many of these age-related conditions.