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Role of the NALP3-inflammasome activation by muramyl dipeptide in vivo

Final Activity Report Summary - NALP3 AND MDP (Role of the NALP3-inflammasome activation by muramyl dipeptide in vivo)

Interleukin-1beta (IL-1b) is a cytokine with major roles in inflammation and innate immune responses. IL-1b is produced as an inactive proform that must be cleaved within the cell and secreted to generate biologically active IL-1b. The enzyme caspase-1 catalyzes the reaction. Recent work showed that caspase-1 must be activated by a complex known as the inflammasome. The inflammasome comprises NALP, which is an intracellular receptor involved in innate immunity, and an ASC adapter that ensures caspase-1 recruitment to the receptor. The most extensively described inflammasome to date is formed by the NALP3 receptor within monocytes and macrophages. In 2005, little was known about the inflammasome inducers and the mechanisms leading to inflammation formation within the cells except that mutations involving the NALP3 gene cause hereditary periodic fever syndromes in humans.

The objective was the characterisation of novel activators of the inflammasome and the molecular mechanism leading to the inflammasome activation.

During the 2 years of research funded by MCA, in collaboration with D. Muruve (Calgary, Canada) we were able to identify adenoviruses and more generally cytoplasmic DNA as potent activators of the inflammasome in innate immune cells. Thus these data shed light on the drawback of using adenovectors as therapeutic vectors. In addition they unraveled a new mechanism through which the inflammasome detects potentially harmful cytoplasmic DNA, strengthening the importance of the inflammasome in innate immunity.

In addition to the work described above, I was able to identify a new mechanism involved in the activation of NALP inflammasome in innate immune cells which is the efflux of potassium (K+). Indeed, upon application of NALP3 inflammasome activator to the cells, there is a requirement for the cellular K+, which is elevated within cells compared with the level found in the intersticial fluid, to go out from the cell in order to induce the formation of the complex. These findings gained insights into the mechanism of activation of the inflammasome and may link the inflammasome to human conditions associated with hyperkalemia (high plasma level of potassium).