NLRP3 inflammasome-driven hemophagocytic lymphohistiocytosis occurs independent of IL-1β and IL-18 and is targetable by BET inhibitors

Shojaee, F; Azadian, E; Wong, MX; Ma, X; Rickard, J; Pang, J; Hall, C; Kueh, AJ; Masters, SL; Rioja, I; Prinjha, RK; Doerflinger, M; Lawlor, KE; Rashidi, M; Vince, JE

Author(s): Shojaee, F; Azadian, E; Wong, MX; Ma, X; Rickard, J; Pang, J; Hall, C; Kueh, AJ; Masters, SL; Rioja, I; Prinjha, RK; Doerflinger, M; Lawlor, KE; Rashidi, M; Vince, JE;
Details: Publication Year 2025-07-11,Volume 11,Issue #28,Page eadv0079
Journal Title: Science Advances
Abstract: 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. 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 interleukin-1β (IL-1β) and IL-18 conferred strong protection from sHLH. Instead, co-deletion of GSDMD and caspase-8-activated GSDME limited sHLH-driven lethality, demonstrating redundancy in the pyroptotic machinery required to induce sHLH. We also found that bromodomain and extraterminal domain (BET) inhibitors prevent NLRP3-driven pyroptosis, which acted by blocking inflammasome priming. BET inhibitors prevented increased NLRP3 levels in diseased tissue, limited the production of sHLH-associated IL-1β, interferon-γ, and tumor necrosis factor, and protected from sHLH pathogenesis. These findings suggest that targeting NLRP3 could limit sHLH and identify clinically relevant bromodomain-selective BET inhibitors capable of eliminating NLRP3-driven pyroptosis and the sHLH cytokine storm.
Publisher: AAAS
Keywords: *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/genetics; *Interleukin-1beta/metabolism/genetics; *Inflammasomes/metabolism; *Interleukin-18/metabolism/genetics; *Lymphohistiocytosis, Hemophagocytic/metabolism/drug therapy/pathology/genetics; Animals; Mice; Pyroptosis/drug effects; Humans; Disease Models, Animal; Mice, Knockout; Phosphate-Binding Proteins/genetics/metabolism
Research Division(s): Inflammation; Blood Cells and Blood Cancer; Infection and Global Health
PubMed ID: 40632844
Publisher's Version: https://doi.org/10.1126/sciadv.adv0079
Open Access at Publisher's Site: https://doi.org/0.1126/sciadv.adv0079
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-07-28 03:09:58

Last Modified: 2025-07-28 03:11:13