NLRP3: Alarm bell in the immune system – and trigger for dangerous inflammation

The NLRP3 protein occurs naturally in the body and is an important component of the immune system. It can be thought of as a sensor that responds to cellular stress: if something in the body is not working as it should, the cells respond with stress – and thus activate NLRP3. This is because NLRP3 recognizes specific signals at the molecular level which indicate a problem. NLRP3 then triggers inflammation in a complex process. Inflammation is an important part of the body's immune response; normally, it helps immune cells function and then induces the healing process to repair any damage caused by illness or injury.However, inflammation can also overreact and become chronic. This happens in gout, diabetes, atherosclerosis, various diseases of the cardiovascular system, and also in neurodegenerative diseases such as Alzheimer’s disease. Despite all their differences, these diseases have one thing in common: the protein NLRP3 plays a central role. It is believed to be chronically activated in these conditions, and continuously produce inflammatory signals that negatively affect disease.

Devastating inflammatory reactions

In the body, NLRP3 is found primarily in myeloid cells, such as macrophages. These immune cells specialize in eliminating harmful substances and pathogens, such as viruses and bacteria. The myeloid cells in the brain are called “microglia.” When NLRP3 sounds the alarm, a highly complex reaction takes place. As a result, NLRP3 combines with other proteins to form an aggregated structure called the “NLRP3 inflammasome,” which triggers the inflammatory response. 

Different stress symptoms in the body can activate NLRP3, depending on the clinical disease. In Alzheimer's disease, for example, it is the increasing concentration of amyloid beta. Researchers at the DZNE were able to demonstrate that NLRP3 is activated in the brain tissue of people with Alzheimer's disease. Subsequent experiments showed that if NLRP3 is removed from a mouse model that mimics Alzheimer’s disease, only mild symptoms of the disease develop. This proved that the protein plays a role in the cascade of Alzheimer's disease. However, study results from the DZNE point to a vicious circle: the accumulation of amyloid beta triggers an ongoing alarm in the immune system, which leads to the formation of the NLRP3 inflammasome, which in turn causes the inflammatory response and that in turn leads to the formation of amyloid plaques. It has also been shown that these inflammatory processes cause so-called tau proteins to become altered and accumulate in nerve cells. This is another characteristic of Alzheimer's disease. The bottom line is that the “fire” ignited by the NLRP3 inflammasome plays a key role in the development of both amyloid and tau pathology.

Inhibitors as a promising treatment 

Scientists hope that diseases can be treated by targeting NLRP3. So-called inhibitors are a particular focus: these are drugs that suppress the function of NLRP3 and prevent it from forming an inflammasome complex. This could potentially reduce or even prevent the inflammation that ultimately leads to serious diseases. Such drugs are currently being tested in clinical trials for various diseases – for gout, for example, but also for Parkinson's disease. An important question here is: if such a drug helps, does it work equally well for gout, Alzheimer's disease, Parkinson's disease, and all the other conditions associated with NLRP3? Or are different treatments needed depending on where in the body the inflammation is triggered?

Researchers hold out great hope for this type of therapy because it targets a very early point in the disease cascade and could potentially prevent its development.