New study solves a long-standing mystery in innate immunity

Dr. Zhijian "James" Chen, biochemist of UT Southwestern and winner of the Breakthrough Award, answers a long-standing question in the field of innate immunity.

Scientists have long wondered how a protein, NLRP3, can promote inflammation in response to a wide range of seemingly unrelated stimuli.

Dr. Chen, Professor of Molecular Biology and Director of the Center for Inflammation Research at UT Southwestern, this month received the Breakthrough Prize in Life Sciences 2019 for the recognition of the cGAS DNA detection enzyme (GMP-AMP cyclic synthase), which rings the alarm sound the alarm. an innate immune response inside the cells.

In this study, published today in NatureDr. Chen has studied another immune system pathway involving the NLRP3 protein, which plays a critical role in cell assembly of the multiprotein complex called inflammation. In response to a plethora of harmful agents ranging from toxins to cholesterol crystals, the inflammasome triggers the path of inflammatory cell death, or pyroptosis of the Greek word pyro, which means fire. The inflammasome also increases the body's production of immune system substances, such as interleukins, which contribute to the immune response of the body.

In addition, the NLRP3 protein underlies inflammation in a group of autoinflammatory diseases called cryopyrin-associated periodic syndromes (CAPS), which includes cold autoimmune family syndrome (FCAS), gout, and a form of inflammation of brain cells associated with Alzheimer's disease.

"A longstanding question in this area is how NLRP3 can be activated by many agents who do not seem to share similar chemical or structural similarities," said Dr. Chen, a researcher at Howard Hughes Medical Institute's George L. Holder. MacGregor Distinguished Chairholder in Biomedical Sciences and Chair of Professor at UT Southwestern's Center for Defense Genetics. "These results provide a new avenue for the development of therapies targeting the NLRP3 pathway for the treatment of inflammatory diseases."

Through a combination of biochemical, imaging and genetic approaches, Dr. Chen and Dr. Jueqi Chen, postdoctoral researcher, the lead author of the study and no relationship, have discovered a previously unknown structural change in the cells.

They discovered that various stimuli caused fragmentation of the cellular organelle called trans-Golgi network (TGN) into giant vesicles, or sacs filled with fluid. These vesicles contain a special lipid component (PI4P) that binds to a specific region of NLRP3. This link triggers a series of events leading to the activation of the inflammasome.

"The inflammation of NLRP3 is unique in that it can be triggered by a wide range of stimuli," said Dr. Chen. "This study shows that rather than directly recognizing harmful agents, the NLRP3 inflammasome detects a structural change caused by a series of different agents causing cellular damage. In fact, the activation of NLRP3 recalls the "protection model" that plants use to control various threats by monitoring host targets that have been modified, the so-called pathogen-induced self-approach.

"By binding to disassembled trans-Golgi vesicles as a modified self, NLRP3 indirectly detects a wide variety of molecules associated with pathogens and hazards," he added.