Additional piece: Understanding the Cellular Process of Inflammation Activation
Inflammation is a critical process in the body’s immune response, helping to protect against harmful pathogens and heal damaged tissues. However, prolonged or chronic inflammation can have detrimental effects on overall health and has been linked to the development of various diseases, including type 2 diabetes, heart disease, and depression. Therefore, understanding the cellular process of inflammation activation is crucial in finding new treatments and interventions to regulate this response.
Researchers at Cedars-Sinai have made significant strides in unraveling the steps involved in the production of IL-1 beta, a potent inflammatory protein signal released during many inflammatory responses. By uncovering these processes, they have opened up possibilities to modulate the type of inflammation associated with infections and inflammatory diseases.
The study conducted by Cedars-Sinai researchers builds upon their previous research from 2016, where they identified the enzyme hexokinase as a key player in the detection of infection. Hexokinase, responsible for converting glucose into energy within cells, was found to have an additional inflammatory function. It binds to a sugar in the bacterial cell wall and activates inflammasomes, receptors of the innate immune system that recognize microbes and tissue damage, ultimately leading to the production of IL-1 beta.
The current research delves deeper into the cellular processes involved in this inflammatory pathway. The team discovered that hexokinase leaves the mitochondria, the cell’s energy powerhouse, initiating an immune response. Its departure destabilizes the mitochondria and triggers the clustering of a channel called VDAC in the mitochondrial membrane. This interaction with another protein called NLRP3 initiates the assembly of inflammasomes, resulting in the production of IL-1 beta.
To better understand the steps in the IL-1 beta pathway, the researchers studied cells derived from laboratory mice. They utilized inhibitors to block specific cell functions and employed gene-editing technology to turn off certain genes and the proteins they express. These experimental approaches enabled them to identify the vital proteins involved in triggering inflammation.
Using the state-of-the-art super-resolution microscope available at the Cedars-Sinai Biobank and Research Pathology Resource, the researchers were able to visualize and measure the different steps of the inflammatory process within cells. This advanced imaging technology provided valuable insights into the dynamics and interactions of the proteins involved in inflammation activation.
The findings of this study are significant as they provide a more complete understanding of the cellular processes that initiate and sustain inflammation. This knowledge is vital in developing targeted interventions and treatments that can specifically modulate the inflammatory response without compromising overall cellular function and energy metabolism.
Moving forward, Cedars-Sinai researchers continue to explore the cellular pathways associated with the activation of inflammasomes by hexokinase. Their aim is to further elucidate the intricacies of this process and leverage their findings to develop therapeutic strategies that can effectively target the inflammatory pathway in various diseases.
Summary:
Cedars-Sinai researchers have made significant progress in understanding the cellular process behind inflammation activation. Through their studies, they have identified the steps leading to the production of IL-1 beta, a potent inflammatory protein signal. The researchers found that the enzyme hexokinase plays a crucial role in the detection of infection, activating inflammasomes responsible for recognizing microbes and tissue damage, ultimately leading to inflammation. By studying cells derived from laboratory mice and utilizing advanced imaging technologies, the researchers gained a better understanding of the dynamics and interactions involved in the inflammatory pathway. This enhanced knowledge paves the way for developing targeted interventions and treatments to regulate inflammation without negatively impacting overall cellular function and energy metabolism.
Additional piece:
Inflammation is a complex biological response that plays a crucial role in our body’s defense mechanisms. It acts as a natural defense mechanism, protecting us from harmful pathogens, foreign invaders, and aiding in tissue repair. When the innate immune system detects a potential threat, it initiates an inflammatory response, characterized by classic symptoms such as swelling, redness, warmth, and pain. In healthy individuals, these symptoms eventually subside as the inflammation resolves.
However, in some cases, the inflammation phase persists, leading to chronic inflammation. Chronic inflammation can have serious consequences, damaging healthy cells and tissues and contributing to the development of various diseases. Among the diseases associated with chronic inflammation are type 2 diabetes, heart disease, and depression. Therefore, understanding the cellular processes behind inflammation activation is of paramount importance in developing effective therapeutic interventions.
The recent findings by Cedars-Sinai researchers shed light on the gradual process that leads to the production of IL-1 beta, a critical inflammatory protein signal. By identifying the role of hexokinase, an enzyme responsible for energy production within cells, in the activation of inflammasomes, the researchers have unlocked new possibilities for modulating inflammation associated with infectious and inflammatory diseases.
Hexokinase’s dual function in glucose metabolism and inflammation highlights the intricate balance between keeping the cell’s energy production intact while controlling the inflammatory response. This dual role emphasizes the need for targeted interventions that focus on the inflammatory aspect, rather than completely inhibiting or turning off hexokinase, which could be detrimental to overall cellular function.
The researchers’ use of cutting-edge techniques, such as super-resolution microscopy and gene-editing technology, has allowed them to visualize and measure the steps involved in the inflammatory process within cells. These advanced imaging tools provide unprecedented insights into the intricate interactions and dynamics of the proteins involved in inflammation activation.
The significance of these findings lies in the potential development of therapies that can specifically target the inflammatory pathway without disrupting the delicate balance of cellular processes. By identifying and manipulating the proteins involved in inflammation activation, researchers may be able to develop interventions that regulate inflammation and mitigate its detrimental effects on overall health.
Moving forward, Cedars-Sinai researchers aim to further explore the cellular pathways associated with the activation of inflammasomes by hexokinase. By understanding these processes in more detail, they hope to uncover new targets for therapeutic intervention and develop personalized treatments for individuals with chronic inflammation.
In conclusion, the recent study by Cedars-Sinai researchers enhances our understanding of the cellular processes involved in inflammation activation. Their findings open up new avenues for developing targeted interventions and treatments for various diseases associated with chronic inflammation. By delving deeper into the intricacies of inflammation at the cellular level, researchers can work towards finding innovative solutions to curb chronic inflammation and improve overall health outcomes.
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Cedars-Sinai researchers have identified several steps in a cellular process responsible for triggering one of the body’s important inflammatory responses. Their findings, published in the peer-reviewed journal science immunologyopens possibilities to modulate the type of inflammation associated with various infections and inflammatory diseases.
Specifically, researchers have improved our understanding of the steps that lead to the production of IL-1 beta, a potent inflammatory protein signal released during many inflammatory responses.
“We now have a clearer understanding of the gradual process that leads to the production of IL-1 beta,” said Andrea Wolf, PhD, assistant professor of Biomedical Sciences and Medicine at Cedars-Sinai, and lead and corresponding author of the new study. “By understanding the process, we hope to one day find a treatment for the diseases associated with this inflammatory response.”
When the innate immune system, the defense system we were born with, identifies a potentially harmful bacterium, virus or other foreign invader, it releases white blood cells to surround and attack the foreign agent. This can cause swelling, redness, warmth, and pain in body tissues that, in a healthy body, eventually go away.
However, some people get stuck in the inflammation phase. This causes what is known as chronic inflammation. Chronic inflammation can damage healthy cells in the body and is believed to lead to serious diseases such as type 2 diabetes, heart disease, and depression.
“Inflammation, in many cases, is vital to a thriving immune system and a healthy body,” said David Underhill, PhD, chair of the Department of Biomedical Sciences and the Janis and William Wetsman Family Chair in Inflammatory Bowel Disease, who is also a a senior and corresponding author of the study. “However, prolonged inflammation can wreak havoc in the body. This underscores the importance of understanding the cellular process of how inflammation is activated so that we can work towards finding new treatments to curb chronic inflammation.”
The study published today is a follow-up to Cedars-Sinai research published in 2016 explaining how cells work to detect infection. In that study, the researchers discovered that an enzyme called hexokinase, which is normally used by cells to convert glucose into energy, has a second inflammatory function. They found that hexokinase binds to a sugar in the bacterial cell wall and activates inflammasomes, leading to the production of IL-1 beta. Inflammasomes are receptors of the innate immune system that recognize microbes and tissue damage.
The current work presents a more complete picture of this process.
The researchers discovered that hexokinase leaves the mitochondria, the part of the cell that generates energy. This initiates an immune response: the release of hexokinase destabilizes the mitochondria and alerts the cell that something is wrong. This leads to the clustering of a channel called VDAC in the mitochondrial membrane, which interacts with another protein called NLRP3 to initiate inflammasome assembly. The inflammasomes then produce IL-1 beta, a driver of inflammation.
The researchers studied cells derived from laboratory mice to understand the steps involved in the IL-1 beta pathway. The team used substances called inhibitors that block cell functions, as well as gene-editing technology to turn off certain genes and the proteins they express. This allowed them to understand which proteins are vital in triggering inflammation.
Cedars-Sinai Postdoctoral Scientist Sung Hoon Baik, PhD, used the super-resolution microscope that is part of the Cedars-Sinai Biobank and Research Pathology Resource to visualize and measure the steps of this inflammatory process within cells. individual.
“Being able to target specific steps in this pathway is vital, because in addition to being important for inflammation, components of this pathway also play vital roles in maintaining energy within the cell,” Wolf said. “We want to focus on its inflammatory role, not just turn it all off, because that would be bad for the cell.”
Researchers continue to study the cellular pathways that lead to and result from the role of hexokinase in the activation of inflammasomes. They are also using the results of this study to start targeting this inflammatory pathway in different diseases.
Other Cedars-Sinai researchers who worked on the study include Courtney Becker, manager of the Underhill Laboratory at Cedars-Sinai; Sarah Fett, Cedars-Sinai Research Associate; and V. Krishnan Ramanujan, PhD, a research associate professor in the Cedars-Sinai Department of Medicine and director of the Cedars-Sinai Biobank.
Funding: The study was funded by the National Institutes of Health (Award numbers R01AI148465, R01GM085796, R01AI071116).
https://www.sciencedaily.com/releases/2023/06/230616162000.htm
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