New study opens pathways for developing inflammation-fighting treatments

Researchers from South Dakota State University's Department of Biology and Microbiology and the BioSystems Networks and Transformative Research Center – Insights into Inflammation (BioSNTRii) have identified a protein — ALIX — that can help boost cells' self-healing abilities. 

When pathogens enter our cells as part of an infection, our body will trigger a programmed cell death known as "pyroptosis" as part of an antimicrobial response. This response also plays a role in processes which are not directly linked to infection, such as chronic inflammation and is most commonly associated with diseases like diabetes and inflammatory bowel disease.

When cells undergo pyroptosis, they form holes or pores in their membranes. These holes serve as a warning sign to the immune system, which then initiates an inflammatory response to protect the body. Scientists have long known about these membrane holes, but little is known about what happens after the holes are formed. Can cells repair themselves and survive, or do membrane holes serve as a fatal end?

Research from South Dakota State University's Department of Biology and Microbiology is shedding new light on this question. Led by assistant professor Gergely Imre, the research team has published a study in Nature's Cell Death and Disease, which describes a protein, ALIX, that can help boost a cell 's self-healing ability to prevent pyroptosis.

"In this study, we provide evidence that membrane permeability is not equal to cell death and can be reversed if the pyroptosis stimulus is removed," Imre explained.

The key is timing. Gasdermin-D is a protein that, when activated, creates holes in the cell membranes. The longer the protein remains in the membrane, the more likely it is to die. But as Imre's research team found, the ALIX protein can help remove Gasdermin-D from the membrane. If the cell removes Gasdermin-D in less than two hours, it can recover — as long as ALIX is present. But if the protein isn't removed, the cell will likely die.

"Our research is aiming at finding ways to be able to boost these cells’ self-healing potential," Imre said. "My team identified a protein, ALIX, that might play an important role in this process."

For those diagnosed with inflammatory bowel disease and other chronic inflammatory conditions, pyroptosis can make matters worse.

"There are chronic inflammatory conditions such as inflammatory bowel disease, where the gut partially loses its function due to the inflammatory death of its cells," Imre explained.

Imre and his research team's work shows that ALIX proteins may be key in preventing the additional challenges that come with chronic inflammatory conditions.

"Our research suggest pyroptosis is reversible," said Prafulla Shrestha, a former graduate research assistant in Imre's lab. "If the stimulus is removed quickly, cells can repair themselves by eliminating these pores. We found that ALIX plays a critical role in this rescue process, acting independently of its usual partner TSG-101, likely through endocytosis."

In particular, this research will open up new pathways for developing inflammation-fighting treatments. It may also help medical scientists find a way to control excessive immune reactions without shutting down the immune system entirely.

“Our findings show that even after pyroptotic damage, cells have the remarkable ability to heal themselves if the right molecular machinery, like ALIX, is in place," said Sylvia Otchere, graduate research assistant in Imre's lab. "As a graduate student leading this project, I’m inspired by how uncovering these fundamental repair mechanisms could eventually inform treatments that help restore tissue health in chronic inflammatory diseases.”

"These findings can lead to the development of new therapeutic strategies in chronic inflammatory conditions by bolstering the cell’s inherent self-healing potential," Imre added.

Contributing authors on this study include SDState faculty members — Imre, Adam Hoppe, Natalie Thiex, Ryan Hanson, Radhey Kaushik— and graduate students — Otchere, Shrestha, Himesh Parmar, Jadyn Perry, Brittany Hofmeister and Michelle Steyn. Jaime Lopez-Mosqueda, a faculty member from the University of Texas and a former member of SDState's Department of Biology and Microbiology, also contributed.

Funding for this research was provided by the National Institutes of Health Center of Biomedical Research Excellence and the U.S. Department of Agriculture’s National Institute of Food and Agriculture.