Mechanism of inflammation initiation through NLRP3 inflammasome activation revealed

Inflammation is the response of our immune system to infection and harmful environmental effects. On one hand, it is beneficial as it defends our body against microbes. On the other hand, excessive inflammation leads to serious diseases. A recent research published in Nature Communications reveals details on inflammation initiation through engagement of protein called NLRP3. Researchers from National Institute of Chemistry, Slovenia together with their Spanish colleagues discovered that a large part of NLRP3 protein is dispensable for detection of danger. They also showed how NLRP3 is regulated. Tight regulation of NLRP3 that is in contrast to other innate immune safeguards triggered predominantly by self-derived molecules might be crucial for suppressing auto-inflammatory response. As NLRP3 is involved in a variety of devastating and incurable diseases such as Alzheimer's disease the insight into NLRP3 activation provides the basis for development of novel therapies and diagnostics methods.

Inflammation is a process known from the beginning of medicine in ancient times. Inflammation can either be triggered by microbes, but can also be induced by tissue damage and harmful substances originating from environment. Inflammation is crucial for defense against evading microbes, yet can also be harmful. Chronic inflammation can lead to serious illnesses such as cancer and degenerative diseases.

Inflammation is driven by innate immune response. Innate immunity contributes to first line defense against invading pathogens. Many innate immune sensors surveil the invading pathogens and clear off infections long before adaptive immunity takes over. However, in some cases the good sensors turn dark, and the NLRP3 sensor is one of the seminal examples of such dualism. NLRP3 sensor upon activation forms an inflammasome, a complex that perpetuates inflammation. The most direct evidence on the pathological role of NLRP3 comes from a group of autoinflammatory diseases, which evolve due to mutations in the NLRP3 gene. However NLRP3 inflammasome also drives inflammation in diseases such as diabetes and Alzheimer's disease and growing evidence shows that NLRP3 is connected to other aging-related conditions.

Usually innate immune sensors recognize relatively specific patterns found on microbes. Some of the sensors respond also to endogenous molecules released upon tissue damage. NLRP3 on the other hand responds to various microbial, self-derived and pollutant molecules. One could say that NLRP3 senses that something is wrong with the cell and responds with inflammation and cell-destruction program to further alarm other cells on the present danger. How NLRP3 is activated is relatively unknown.

Researchers from Department of Synthetic Biology and Immunology at National Institute of Chemistry, Slovenia, headed by Prof. Roman Jerala, together with Spanish colleagues now provide important clues on the role of NLRP3 domains in the mechanism of activation and regulation. In contrast to what is known for other innate immune sensors, researchers show that a large part of NLRP3 protein is unnecessary for response to triggers and inflammasome activation. This provides a more defined target for development of anti-inflammatory drugs. They also provide other details on the regulation of NLRP3 inflammasome activation. The lead researcher Dr. Iva Hafner Bratkovič explains: "This study evolved from our interest on inflammation in neurodegenerative diseases. NLRP3 is the key innate immunity player in chronic inflammation. Its role has been shown in a variety of diseases from cardio-vascular to neurodegenerative. Development of efficient and safe NLRP3 inhibitors that specifically target NLRP3 inflammasome activation might lead to important drugs for a variety of currently incurable diseases."

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