WEHI PhD Completion Seminar hosted by Professor James Vince

Farzaneh Shojaee

PhD Student – Vince Laboratory, Inflammation division, WEHI

Defining the Cell Death and Inflammatory Pathways in a Cytokine Shock Syndrome

 

Davis Auditorium

Join via SLIDO enter code #WEHIphdcompletion

Including Q&A session

Followed by refreshments in Tapestry Lounge

Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal cytokine storm syndrome. Its high mortality rate reflects limited therapeutic options and a poor understanding of disease-causing signaling. Here, we show that the NLRP3 inflammasome is responsible for increased mortality in a model of secondary HLH (sHLH). Unexpectedly, neither deletion of the NLRP3-activated pyroptotic effector, GSDMD, nor combined deletion of the inflammasome-activated cytokines, IL-1β and IL-18, conferred protection from sHLH. Instead, co-deletion of pyroptotic GSDMD and GSDME limited sHLH-driven lethality, demonstrating redundancy in the pyroptotic machinery required to induce sHLH. Importantly, we also discovered that BET inhibitors prevent NLRP3-driven pyroptosis, which acted by blocking inflammasome priming. Accordingly, BET inhibitors prevented increased NLRP3 levels in diseased tissue, and reduced sHLH disease severity.

These findings suggest that targeting NLRP3 could offer greater benefit in sHLH compared to inhibiting inflammasome-activated cytokines and identify clinically relevant bromodomain-selective BET inhibitors as novel agents able to eliminate NLRP3-driven pyroptosis.

All welcome!