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.

Identifying the molecular Switch for NLRP3 Inflammasome - Medicine Innovates

About the author

Danica Chen is an Associate Professor of Metabolic Biology, Nutritional Sciences & Toxicology at University of California at Berkeley, a member of Berkeley Stem Cell Center, and a member of QB3 Consortium in Lifespan Extension. She was a Searle Scholar, an Ellison Scholar, a Kavli Fellow, and a Hellman Fellow. Dr. Chen received Ph.D. in molecular and cell biology from University of California at Berkeley and obtained postdoctoral training in biology at Massachusetts Institute of Technology.

Her research aims to understand the molecular and cellular mechanisms underlying aging-associated conditions and elucidate which aspects of aging-associated conditions are reversible. Recent studies from her lab have revealed mitochondrial stress as a cause of stem cell exhaustion and tissue degeneration during aging.

She identified mitochondrial stress resistance programs that become dysregulated in aged stem cells, and demonstrated these programs can be targeted to improve survival and regenerative capacity of aged stem cells. These findings give hope for targeting aging-associated dysregulated cellular protective programs, such as the pathways regulated by NAD+-dependent enzymes sirtuins and NAD+ replention, to reverse stem cell aging, tissue degeneration and dysfunction.


Ming He, Hou-HsienChiang, Hanzhi Luo, Zhifang Zheng, Qi Qiao, Li Wang, Mingdian Tan, Rika Ohkubo , Wei-Chieh Mu, Shimin Zhao, Hao Wu, Danica Chen. An Acetylation Switch of the NLRP3 Inflammasome Regulates Aging-Associated Chronic Inflammation and Insulin Resistance. Cell Metabolism, Vol 31, 3, 2020, Pages 580-591.e5.

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