Inflammation Results from a Cellular Process; Research Says

Cedars-Sinai researchers have discovered numerous phases in a cellular process that is responsible for generating one of the body’s critical inflammatory responses. Their findings, which were published in the journal Science Immunology, suggest that there may be ways to modulate the type of inflammation associated with certain infections and inflammatory illnesses.

The researchers specifically enhanced their understanding of the mechanisms that lead to the creation of IL-1 beta, a powerful inflammatory protein signal generated during various inflammatory responses.

“We now have a clearer understanding of the stepwise process that leads to the production of IL-1 beta,” said Andrea Wolf, Ph.D., assistant professor of Biomedical Sciences and Medicine at Cedars-Sinai, and a senior and corresponding author on the new study. “By understanding the process, we hope to one day find a treatment for diseases associated with this inflammatory response.”

When our innate immune system detects a potentially hazardous bacterium, virus, or other external invader, it sends out white blood cells to surround and attack the foreign agent. This might produce swelling, redness, heat, and pain in the body’s tissues, which will gradually go away in a healthy body.

However, some people become stuck in the inflammatory phase. Chronic inflammation arises as a result of this. Chronic inflammation can harm healthy cells in the body and is linked to major diseases such as type 2 diabetes, heart disease, and depression.

“Inflammation, in many instances, is vital to a thriving immune system and healthy body,” said David Underhill, Ph.D., chair of the Department of Biomedical Sciences and the Janis and William Wetsman Family Chair in Inflammatory Bowel Disease, who is also a senior and corresponding author on the study. “However, prolonged inflammation can wreak havoc on the body. This underscores the importance of understanding the cellular process of how inflammation is activated so we can work toward finding new treatments to curb chronic inflammation.”

The research builds on Cedars-Sinai research published in 2016 that explains how cells detect infection. In that study, researchers discovered that an enzyme known as hexokinase, which is normally employed by cells to turn glucose into energy, also has an inflammatory function. They discovered that hexokinase attaches to a sugar in bacteria’s cell wall and activates inflammasomes, resulting in the generation of IL-1 beta. Inflammasomes are innate immune system sensors that sense pathogens and tissue injury. The recent work provides a more comprehensive view of this process.

The researchers observed that hexokinase exits the mitochondria, the component of the cell that produces energy. This initiates an immunological response: Hexokinase release destabilizes the mitochondria and notifies the cell to a problem. This causes a channel called VDAC to cluster in the mitochondrial membrane, where it interacts with another protein called NLRP3 to trigger inflammasome assembly. The inflammasomes then create IL-1 beta, a pro-inflammatory factor.

The researchers investigated cells generated from laboratory mice to better understand the steps involved in the IL-1 beta pathway. To turn off certain genes and the proteins they express, the researchers used inhibitors, which impede biological processes, as well as gene-editing techniques. This enabled them to determine which proteins are essential for inducing inflammation.

Sung Hoon Baik, Ph.D., a Cedars-Sinai postdoctoral scientist, employed a super-resolution microscope from the Cedars-Sinai Biobank and Research Pathology Resource to view and measure the phases of this inflammatory process within individual cells.

Being able to target specific steps in this pathway is vital, because in addition to being important for inflammation, the components of this pathway also play a vital role in maintaining energy within the cell,” Wolf said. “We want to home in on its inflammatory role, not just turn it all off, because that would be bad for the cell.”

The researchers are still researching the cellular stages that lead up to and result from hexokinase’s participation in inflammasome activation. They are also leveraging the findings of this study to begin targeting this inflammatory pathway in various disorders.

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