Deacetylation of the NLRP3 Inflammasome as a Way to Control Chronic Inflammation

Chronic inflammation is an important component of degenerative aging. Excessive inflammatory signaling and activation of the immune system arises due to a combination of many factors, of which some are more important than others, such as the presence of lingering senescent cells. Most of the research focused on controlling inflammation is more interested in sabotaging the mechanisms of control than in removing root causes, however. The work here is an example of the type, in which scientists identify an important feature of the regulatory system controlling inflammation. Forcing a sizable reduction of inflammation via this regulatory system is a fairly blunt tool, as some degree of transient inflammation is vital to health, such as in the response to infection or injury. Nonetheless, the benefits may be large enough to outweigh the side-effects, as is the case for a number of past approaches to limiting inflammation in, for example, the treatment of autoimmune conditions.

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. Researchers now show that a bulky collection of immune proteins called the NLRP3 inflammasome - responsible for sensing potential threats to the body and launching an inflammation response - can be essentially switched off by removing a small bit of molecular matter in a process called deacetylation. Overactivation of the NLRP3 inflammasome has been linked to a variety of chronic conditions, including multiple sclerosis, cancer, diabetes, and dementia. The 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 mice and immune cells called macrophages, the 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. 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 actually reverse the course of metabolic disease.

"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. I think this finding has very important implications in treating major human chronic diseases. 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 aging-related conditions and use that knowledge to aid a drug development for aging-related diseases."

Link: https://news.berkeley.edu/2020/02/06/molecular-switch-reverses-chronic-inflammation-and-aging/

Comments

Immunosuppressants used in transplantation could be tailored/changed a bit to reduce the immune system overdrive. Rapamycin, Ciclosporin,

Posted by: thomas.a at February 13th, 2020 7:54 AM

but SIRT2 inhibitors have been found to be protective in models of Parkinson's ...

MCC950 inhibits NLRP3 & was found to improve motor function in mouse models of PD

Posted by: CD at February 13th, 2020 2:58 PM

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