Transcriptional regulation of inflammasomes
As a lab, we like to use unbiased genome-wide CRISPR-Cas9 screen to uncover novel molecular players in our favorite inflammatory pathways. Lipopolysaccharide (LPS) is a key constituent of Gram negative bacteria and one of the major PAMP detected by the immune system to detect and respond to bacteria. While this is key to fight bacterial infection, it can also trigger septic shock and a lethal cytokine storm.
In this project, we used direct delivery of Lipopolysaccharide into the host cytosol to trigger activation of the caspase-4 inflammasome and identify genes required for pyroptosis. Three genes came out: 1-Caspase-4, the sensor of LPS and the effector of the non-canonical inflammasome in human cells. 2-GasderminD, the cell death executioner. 3-IRF2, a transcription factor.
We then demonstrated that in human cells IRF2 regulates Caspase-4 levels and in the presence of Interferon, cooperates with IRF1 to control caspase-4 expression.
This work which you can read in greater details here highlights a key regulatory mechanism of human inflammasomes.
We are now pursuing this projet to understand how this regulation takes place in different cell types and what is the relevance of this regulation at steady state and during several inflammatory conditions.
See also our recent review for a broader view of transcriptional regulations of inflammasomes.