Investigating the Innate Immune Receptor NLRP6 with Dr. Chen Shen

How does our immune system protect us against the threats that infiltrate our bodies? This fundamental question of immunology has great urgency today as we fight the COVID-19 pandemic. When the body is challenged by different pathogens, the innate immune system activates a series of receptors to identify specific molecules and mount a defense against the invaders.

How the immune system does this isn’t entirely clear though. To shed light on the mechanisms of innate immunity, CRI postdoctoral fellow Chen Shen, PhD, who works in the lab of Hao Wu, PhD, at Boston Children’s Hospital, is examining an immune receptor named NLRP6, which can help the immune system recognize bacteria or viruses that have invaded the intestines and may also be able to help protect the body from inflammatory diseases like cancer.

Arthur N. Brodsky, PhD:

When it comes to cancer immunotherapy, much of the focus has been on the adaptive immune system, especially the T cell that are able to precisely target and eliminate tumor cells. But in some ways, these adaptive immune responses may not be possible without the innate immune system, which primes and sets the stage for the adaptive response. ­­

So, what does the innate branch of the immune system do, and what is its role in our overall immune functioning and health?

Chen Shen, PhD:

The innate immune system is our body’s first line of defense. After a threat is encountered, innate immune cells like macrophages and neutrophils identify and remove foreign substances and can also recruit other immune cells to sites of injury, infection, or cancer. These macrophages can also digest fragments of proteins from the threat and then present them to T cells, which can then launch an adaptive immune response.

A very important feature of innate immunity is the expression of what are called pattern recognition receptors, or PRRs, that recognize patterns associated with threats as well as the tissue damage caused by them. Toll-like receptors, or TLRs, are one type of PRR. Some TLRs can sense a molecule known as lipopolysaccharide, or LPS, that is a crucial component found on the surfaces of many different types of bacteria. Others are involved in sensing viral RNA as well as the protein subunit in the flagella that bacteria use to move around.

Arthur N. Brodsky, PhD:

That’s interesting. So, the innate immune system is designed to recognize threats that have been commonly encountered in the past, and to do so it targets certain molecules that are generally associated with bacteria or viruses, right? 

Chen Shen, PhD:

Correct.

Arthur N. Brodsky, PhD:

So, another type of PRR involved is detecting these “danger signals” is called NLRP6, which is the focus of your work. What exactly does NLRP6 do and what have you learned about it so far?

Chen Shen, PhD:

Yes, NLRP6 is a very common and important innate immune receptor that is expressed primarily by cells in our intestines, which are in frequent contact with bacteria, viruses, and other potential threats that we’ve ingested. It has several functions, including assessing bacterial byproducts for signs of danger as well as regulating the activity of our mucosal cells that act as a barrier between the intestines and the rest of the body.

In mammals, NLRP6 has also been shown to be involved in the activation of structures called inflammasomes that help the immune system clear bacteria. In our lab, we discovered that NLRP6 directly interacts with double-stranded RNA and plays an important role in this inflammasome activation in these intestines as well as in the liver and lungs.

Arthur N. Brodsky, PhD:

Although NLRP6 is expressed in several organs, you’re focusing on its role in the intestines. Is the gut special in some way with respect to immunity?

Chen Shen, PhD:

Well, we knew that NLRP6 was a very important molecule when it comes to regulating homeostasis in the intestines, especially by influencing the composition of the “good” bacteria within the gut. This collection of beneficial bacteria—collectively known as the gut microbiota—is a very hot topic these days, as it’s been shown to influence not only the development of tumors, but also how they respond to treatment.

This may be partly due, as I mentioned earlier, to NLRP6’s ability to influence the mucosal cells that protect our intestines from other potentially harmful bacteria. Additionally, by protecting intestinal cells against viral infection, NLRP6 may prevent an inflammatory cascade that can damage healthy cells and even promote the development of colorectal cancer. So, in a very real sense, gut immunity is different from the immunity in our blood because of its specific features, such as the mucosa system that acts as a first layer of defense against invading viruses or bacteria.

Arthur N. Brodsky, PhD:

How about NLRP6’s role in organs other than the gut? Our lungs and airways especially come to mind given that they are also exposed to the outside world and foreign bacteria and viruses. Do we know anything about the possible role that NLRP6 might play in response to infections in our throat and lungs?

Chen Shen, PhD:

Yes, NLRP6 can actively regulate our lungs’ ability to defend against infection by certain bacteria and viruses. This is done by activating inflammasomes and by recruiting neutrophils, which suggests that, in some cases, NLRP6 may actually exacerbate the symptoms of pneumonia caused by certain threats. This discovery is certainly interesting in the context of the novel SARS-CoV-2 coronavirus that causes COVID-19, because this virus also appears to result in severe inflammation that can damage the patient's lungs.

Thus, NLRP6’s ability to sense viruses in the lungs might be the next interesting topic we pursue in our lab. Already, we have hypothesized that viral RNA activates NLRP6-dependent inflammasomes in the lungs and may cause some tissue damage. That knowledge allows us to think about some therapeutic strategies that might be able to defend against the damage.

Arthur N. Brodsky, PhD:

That is such a great example of how basic immunology research has the potential to yield solutions to challenges we aren’t even aware of yet. These insights into NLRP6’s identity haven’t led to any therapies for humans yet, but as you and others learn more about this important aspect of the innate immune system, how might your contributions eventually enable us to help patients in the clinic?

Chen Shen, PhD:

In my case, the first step will be to develop mouse models that will allow me to characterize how NLRP6-dependent virus sensing leads to the activation of inflammasomes. Second, I want to extend our studies to other tissues, such as the lungs, that express NLRP6 to protect against viruses.

Arthur N. Brodsky, PhD:

Before we wrap up, could you talk a little bit about how important CRI’s support has been for you when it comes to pursuing this fundamental immunology research?

Chen Shen, PhD:

CRI's support is extremely important because the study of basic immunology is such a crucial area of research, especially when it comes to the molecular details and mechanisms at work. In my case, I’m aiming to find the central targets in the innate immune system’s network of pathways that work to protect us. Hopefully, the discoveries made here can inform the future design of potential therapeutic strategies to fight against a wide range of diseases caused by infection, including some cancers.

Meanwhile, another benefit of basic immunology research is that, as we’re working to characterize the precise ways in which these molecules interact, it also provides a very good screening strategy for future drug discovery because now we can directly observe and analyze the interactions between different drugs and targets.

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