NLRP3 balance: St. Jude researchers pinpoint key innate immune system regulator

Understanding TAK1’s effect on the immune response could lead to new cancer treatments

Almost a decade ago, my research team at St. Jude’s Department of Immunology solved some of the mysteries surrounding a protein complex known as the NLRP3 inflammasome. Our research revealed that the main function of the NLRP3 inflammasome is to assist the immune system in recognizing threats and quickly preparing a defense, whether the threat is from pathogens or damage-associated stressors at the cellular level. In contrast to its protective role against pathogens, elevated active NLRP3 levels were found to be associated with various inflammatory disorders and development of some types of cancer.

Despite discovering the function of NLRP3 12 years ago, researchers are still searching to identify upstream regulators that dictate NLRP3 activation and its functions. Findings from our recent research, published earlier this year in the Journal of Experimental Medicine, identified an enzyme called TAK1 (TGF-β activated kinase-1) as a chief regulator of NLRP3 balance (homeostasis). Armed with this information, researchers may now move forward and explore the effectiveness of modulating TAK1 function for therapeutic purposes including cancer treatment.

How TAK1 could save lives

Before our recent publication, it was well accepted that NLRP3 normally needs two signals for its activation. It was Prajwal Gurung, Ph.D., then a postdoctoral fellow in my lab, who recognized the surprising relationship between NLRP3 and TAK1. TAK1 promoted NLRP3 quiescence and as such, the absence of TAK1 (genetic deletion or chemical inhibition) led to spontaneous NLRP3 activation.

When a TAK1 inhibitor was used in preclinical models, cell proliferation was reduced suggesting that these compounds have the potential to be used against cancer cells. While investigating the antiproliferative effects of TAK1 inhibition, our research also uncovered the contribution of other molecules, especially TNF and RIPK1. Upon TAK1 inactivation, TNF and RIPK1 drive robust inflammasome activation and a potent form of inflammatory cell death, which aid in immune system activation to fight against infections and cancer.

A balancing act

The kinase TAK1 is known to promote inflammation, but my team and I discovered that it can also suppress inflammation. Although, it sounds confusing, but it makes complete sense when we look at it from homeostasis standpoint. The NLRP3 inflammasome helps the battle against pathogens by increasing inflammatory response. Persistent elevated activation of inflammasome will lead to harmful inflammation. The TAK1 function in maintaining NLRP3 homeostasis is critical for preventing unnecessary inflammation. Given our discovery that TAK1 deficiency promotes spontaneous activation of NLRP3, therapeutic strategies that modulate TAK1 might be used to block the spontaneous activation of the NLRP3 inflammasome and therefore block the undesired effects. Because of its potential to induce tumor cell death, TAK1 inhibition may also have implications in cancer immunotherapy. Figuring out the best way to regulate the immune system to the patient’s advantage will be the focus of continued research in this field.