How cellular structures help orchestrate inflammasome activation

Lead authors of the review (L-R) Shouya Feng, Cheng Shen, and Abhimanu Pandey at JCSMR
19 July 2021

When a cell detects “danger” signals, such as microbes or microbial products, it assembles a type of multi-protein complexes called inflammasomes to coordinate the immune defence.

There are many types of inflammasomes, each comprising a sensor protein that activates once it recognizes specific “danger” signals. An inflammasome sensor protein termed NLRP6, for example, is activated by specific microbial metabolites. Upon their activation, inflammasomes induce inflammation and cellular death to eliminate the threat and prevent the spread of infection.

Researchers have identified components needed for inflammasome assembly and activation in various cell types, ranging from immune cells to epithelial cells. However, the reason why different inflammasome types are activated in different cell types is not fully understood.

Some have proposed that specific inflammasome complexes exist in certain cell types to coincide with the natural pathogens of those cells. For example, NLRP6 is found in intestinal cells, where it could detect pathogens that can potentially cause gastrointestinal disease.  

In a recent review published in the journal Trends in Cell Biology, Abhimanu Pandey, Cheng Shen and Shouya Feng – PhD candidates working with Prof Si Ming Man – discuss the many reasons that influence differential inflammasome expression and activation in different cell types. These include exposure to different activating signals, expression of different “helper” proteins, and involvement of cellular organelles.  

Organelle involvement

The authors specifically highlight how cellular organelles help initiate and contribute to this process. For example, besides their major role in generating energy to sustain cellular functions, mitochondria appear to play a part in inflammasome activation.

Mitochondrial membrane proteins can provide a scaffold for the recruitment of inflammasome components, facilitating complex formation and activation. Additionally, molecules such as DNA released from damaged mitochondria and mitochondria-generated Reactive Oxygen Species, a class of highly reactive chemicals, can act as signals for inflammasome activation.

Evidence suggests that the endoplasmic reticulum and Golgi apparatus, responsible for protein synthesis and transport, also control inflammasome signalling. Some proteins in these organelles help recruit inflammasome components, whereas others in their membranes can act as anchors for inflammasome assembly.

Perhaps more obviously, the cytoskeleton, which consists of protein filaments that help transport across the cell, contributes to inflammasome assembly by aiding components to move toward assembly sites. 

Importantly, inflammasome components are found in virtually all organelles but often orchestrate cell-specific inflammasome responses.

Mysteries ahead

To elucidate why and how this happens, researchers often need to introduce genetic deletion or inhibition of different inflammasome components in diverse cell types. Such studies are expensive and time-consuming, but they offer the possibility of identifying specific components that may become the key to treating human diseases associated with abnormal inflammasome activation.

In this respect, the Man group is trying to address some specific questions. Abhimanu and Cheng are currently investigating the role of inflammasomes in cells lining the gut to understand why they become cancer cells and causes colorectal (bowel) cancer. Their work has the potential to identify new ways to stop the development of bowel cancer, a devastating disease that affects 20,000 Australians every year. 

Meanwhile, Shouya is looking into how pathogens play “hide and seek” within immune cells to avoid inflammasome activation and continue the infectious cycle. With the immune system as a blueprint, she is developing drugs and testing their ability to destroy pathogens hiding within immune cells.   

“We hope that a better understanding of how inflammasomes are activated in different types of cells in the body will allow us to find ways to design better drugs to treat patients with infectious disease and cancer,” said Prof Man.