Irvine, Calif., July 16, 2024 — In a significant breakthrough, researchers from the UC Irvine Charlie Dunlop School of Biological Sciences have published a pioneering study in the journal iScience. The study, led by Assistant Professor Reginald McNulty, introduces a novel approach to preventing inflammation-related diseases by targeting a key protein involved in the body’s inflammatory response.
Inflammation is a natural response of the body’s immune system to infection and injury. However, when this response becomes prolonged or unregulated, it can lead to severe health conditions such as septic shock, organ failure, fibrosis and even cancer. A critical player in this process is the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, a multi-protein complex that mediates inflammation.
The core challenge addressed by this research is the overactivation of the NLRP3 inflammasome, which has been implicated in numerous diseases. Despite recent advances, the consequence of oxidized DNA interacting with NLRP3 was not fully understood until now. The Dunlop School team discovered that small molecule inhibitors can bind to NLRP3, effectively preventing its interaction with oxidized DNA which decreases inflammasome activation and reduces inflammation.
“Our study reveals a previously unknown function of the inflammasome protein NLRP3: its ability to cut damaged DNA,” explained Angie Lackner, the study’s first author and a PhD student in the lab of Professor McNulty. “By identifying novel structural and sequence similarities between NLRP3 and the DNA repair protein hOGG1, we uncovered a new active site and potential drug target on NLRP3. This insight allowed us to repurpose existing drugs, initially designed to inhibit hOGG1, to also inhibit NLRP3. Our comprehensive study highlights a new role for the NLRP3 pyrin domain and opens up exciting avenues for drug development.”
The methodology involved in this research combined structural analysis and functional validation inside macrophages to understand how these small molecules interact with NLRP3. They demonstrated that these inhibitors not only bind to NLRP3 but also prevent its interaction with oxidized mitochondrial DNA, thereby blocking inflammasome activation in cellular models.
“This discovery is particularly rewarding as it opens many exciting and unexplored research questions,” said Professor McNulty. “Key future research will involve testing how these drugs work in NLRP3 animal disease models and determining the structural impact of oxidized DNA on NLRP3. This discovery is part of proving that I am capable of adding new pieces to the ever-growing NLRP3 inflammasome scientific puzzle for decades to come.”
PhD student Julia Cabral, another collaborator on the study, added, “Our paper provides a fresh perspective that will help researchers explore the mechanism of NLRP3’s interaction with oxidized DNA. This finding not only deepens our understanding but also opens new doors for potential therapeutic treatments.”
The potential applications of this research are vast. By inhibiting the NLRP3 inflammasome, these small molecules could provide new treatments for a variety of inflammation-related conditions, including metabolic diseases, rheumatoid arthritis and certain cancers. The study’s findings could lead to the development of new drugs that significantly improve the quality of life for patients suffering from chronic inflammatory diseases.
About the University of California, Irvine Charlie Dunlop School of Biological Sciences: Recognized for its pioneering research and academic excellence, the Charlie Dunlop School of Biological Sciences plays a crucial role in the university’s status among the nation’s top 10 public universities, as ranked by U.S. News & World Report. It offers a broad spectrum of degree programs in the biological sciences, fostering innovation and preparing students for leadership in research, education, medicine and industry. Nestled in a globally acclaimed and economically vibrant community, the school contributes to the university’s impact as Orange County’s largest employer and a significant economic contributor. Through its commitment to exploring life’s complexities, the School of Biological Sciences embodies the UCI legacy of innovation and societal impact. For more on the Charlie Dunlop School of Biological Sciences, visit https://www.bio.uci.edu/.