NLRP11: a missing link for human NLRP3 inflammasome activation

Work done in the lab of Prof. Christian Stehlik and Dr. Andrea Dorfleutner at Cedar-Sinai Medical Center, Los Angeles, USA

About author

Savita Devi received her doctorate and Master’s degree from University of Hyderabad, India, where she identified a novel mechanism employed by Helicobacter pylori to evade robust immune activation by exploiting the functional plasticity of innate immune receptors. Later she relocated to the USA for her postdoctoral research at Cedars-Sinai Medical Center in Los Angeles, CA in the lab of Prof. Christian Stehlik and Dr. Andrea Dorfluetner; where she is working on mechanisms regulating the activation of canonical and non-canonical inflammasome.

Interview

How would you explain your research outcomes to the non-scientific community?

Human body encounters trillions of germs and foreign particles every day and our immune system keeps us safe by defending against these substances. Immune system comprises different types of cells and one of them is white blood cells which patrols the body and detects any unwanted foreign substance and releases some chemicals to destroy them which induces inflammation. Some of its key features are redness, swelling with heat/pain and disturbance of tissue homeostasis.

Inflammation is an underlying cause of a diverse set of human diseases, from as minor as fever to as fatal as cancer. Inflammation is beneficial when induced in a controlled manner which clears infections and signifies a healthy immune system; however, it can also be detrimental if it gets uncontrolled and persists chronically. Therefore, it is pivotal to study how exactly inflammation happens and what are the mechanisms which regulate inflammation. In our study, we have shown that the key to controlling the inflammatory response and preventing chronic inflammation may lie in being able to influence the expression of the NLRP11 gene. The NLRP11 gene is not present in mice and is only expressed (present) in humans or higher primates which suggests its integral role in the complex human immune system.

To understand a detailed function of NLRP11, we have used CRISPR/Cas9 method (a system used for gene editing) to remove NLRP11 gene or introduce gene mutation in human white blood cells called macrophages. We have found that upon deletion of NLRP11; innate immune sensor known as NLRP3 inflammasome would not get activated and dampens a strong inflammatory response.

How do these findings contribute to your research area?

NLRP3 is a global innate immune sensor and why it is known as so because it senses a huge variety of pathogens and danger signals indirectly. And when a sensor gets activated by any stimuli without any proper interactions, it needs to be regulated in a tight manner to avoid any unwanted inflammatory response. Our discovery has advanced the field by shedding some light on human NLRP3 inflammasome activation and regulation. This would allow for the development of novel targeted therapies.

“Our discovery has advanced the field by shedding some light on human NLRP3 inflammasome activation and regulation.”

What was the exciting moment during your research?

There were many, however, one that I remember in particular is, when I observed that upon deletion of the pyrin domain of NLRP11 in THP-1 cells, it loses the interaction/binding with NLRP3.

What do you hope to do next?

Next, we are planning to make NLRP11 transgenic mice and test if these mice are more prone to inflammation or inflammatory disease.

Where do you seek scientific inspiration from?

There are multiple little things that inspire me daily, but my foremost inspirations are my parents and my internal drive to contribute to the field of science. Also, I truly believe that not many people get the opportunity to do what they really want; therefore, one should always make the best use of time and give their best.

How do you intend to help Indian science improve?

Given the opportunity, I would come back and establish my own research group in India and do some amazing science, which would be a direct contribution from my end. Also, I believe interdisciplinary collaborations is the key to do innovative and high-quality science, considering the fact of limited funding. Together with this, I would also reach out to young kids in rural areas which might develop their interests towards science and technology; hence I would take some time out to nurture early talents.

Reference

Gangopadhyay, A*., Devi, S*., Tenguria, S*. et al. NLRP3 licenses NLRP11 for inflammasome activation in human macrophages. Nat Immunol 23, 892–903 (2022). https://doi.org/10.1038/s41590-022-01220-3. * These authors contributed equally.

Copy Editor

Anjali Mahilkar

Postdoc

Anjali is a CSIR Senior Research Fellow and a PhD student at IIT Bombay. Her research focuses on answering the question of where do new species come from? There are ~10 million complex species on the planet, and in her graduate work, she works towards understanding the molecular basis that leads to the birth of a new species. She is also interested in understanding how randomness decides evolutionary fates of a population, and if microorganisms can be trained to “learn” and “anticipate” environmental changes. Prior to joining the PhD program, Anjali completed her Masters from IIT Kanpur and Bachelor’s from NIT Raipur. She also had short work stints at Dr. Reddy’s Institute of Life Science and at a Central University in Chhattisgarh. Although not an avid reader, she likes to read fiction in her free time.

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