Researchers at the University of Texas Southwestern Medical Center have discovered how DNA can trigger immune and autoimmune responses from within cells by discovering the DNA sensing enzyme cGAS.
The NLRP3 protein is the basis for inflammation of a group of autoinflammatory diseases called cryopyrin protein-associated periodic syndrome (CAPS), including familial cold urticaria (FCAS), gout and an Alzheimer's disease and disease-related brain cell inflammation. In order to cope with excessive harmful substances, including toxins and cholesterol crystals, the inflammatory body initiates the path of inflammatory cell death. Inflammatory bodies also increase the body's immune system substances, such as interleukins, which contribute to the body's immune response.
"A long-standing problem in this area is how NLRP3 is activated by many different drugs that do not appear to have any chemical or structural similarities," the researchers said.
They discovered a previously unknown structural change in NLRP3 in the cell through imaging and genetic methods. They found that different stimuli caused an organelle called the reverse Golgi network to split into giant vesicles or fluid vesicles. These vesicles contain a special lipid component (PI4P) that binds to specific regions of NLRP3, and their binding triggers a series of events that lead to inflammatory body activation.
"The uniqueness of the NLRP3 inflammatory corpuscle is that it can be stimulated by a large number of stimuli," the researchers said. "This study found that the NLRP3 inflammatory body does not directly recognize harmful substances, but rather detects the structural changes caused by a series of different compounds that cause cell damage. In fact, the activation of NLRP3 is reminiscent of the plant's 'guard model', a model that counters threats by detecting host targets that have been altered, so-called pathogen induction."
"The NLRP3 indirectly perceives various pathogens and dangerous molecules by disassembling the reverse Golgi tube network," the researchers added.
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