2. Academic Validation
  3. A1 is induced by pathogen ligands to limit myeloid cell death and NLRP3 inflammasome activation

A1 is induced by pathogen ligands to limit myeloid cell death and NLRP3 inflammasome activation

  • EMBO Rep. 2023 Oct 17:e56865. doi: 10.15252/embr.202356865.
Mary Speir # 1 2,  Hazel Tye # 1 2,  Timothy A Gottschalk # 1 2,  Daniel S Simpson 3 4,  Tirta M Djajawi # 1 2,  Pankaj Deo # 5,  Rebecca L Ambrose 1 2,  Stephanie A Conos 1 2,  Jack Emery 1 2,  Gilu Abraham 5,  Ashlyn Pascoe 1 2,  Sebastian A Hughes 3,  Ashley Weir 3 4,  Edwin D Hawkins 3 4,  Isabella Kong 3 4,  Marco J Herold 3 4,  Jaclyn S Pearson 1 2 6,  Najoua Lalaoui 3 4,  Thomas Naderer # 5,  James E Vince # 3 4,  Kate E Lawlor 1 2 3 4
Affiliations

Affiliations

  • 1 Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia.
  • 2 Department of Molecular and Translational Science, Monash University, Clayton, VIC, Australia.
  • 3 The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
  • 4 Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.
  • 5 Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia.
  • 6 Department of Microbiology, Monash University, Clayton, VIC, Australia.
  • # Contributed equally.
PMID: 37846472 DOI: 10.15252/embr.202356865
Abstract

Programmed cell death pathways play an important role in innate immune responses to Infection. Activation of intrinsic Apoptosis promotes infected cell clearance; however, comparatively little is known about how this mode of cell death is regulated during infections and whether it can induce inflammation. Here, we identify that the pro-survival Bcl-2 Family member, A1, controls activation of the essential intrinsic apoptotic effectors Bax/Bak in macrophages and monocytes following Bacterial lipopolysaccharide (LPS) sensing. We show that, due to its tight transcriptional and post-translational regulation, A1 acts as a molecular rheostat to regulate Bax/BAK-dependent Apoptosis and the subsequent NLRP3 inflammasome-dependent and inflammasome-independent maturation of the inflammatory cytokine IL-1β. Furthermore, induction of A1 expression in inflammatory monocytes limits cell death modalities and IL-1β activation triggered by Neisseria gonorrhoeae-derived outer membrane vesicles (NOMVs). Consequently, A1-deficient mice exhibit heightened IL-1β production in response to NOMV injection. These findings reveal that bacteria can induce A1 expression to delay myeloid cell death and inflammatory responses, which has implications for the development of host-directed antimicrobial therapeutics.

Keywords

BCL-2A1; NLRP3; TLR ligation; mitochondrial apoptosis; myeloid cells.

Figures
Products