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

• Published in: EMBO reports 2023-11, Vol.24 (11), p.e56865-e56865
• Main Authors: Speir, Mary, Tye, Hazel, Gottschalk, Timothy A, Simpson, Daniel S, Djajawi, Tirta M, Deo, Pankaj, Ambrose, Rebecca L, Conos, Stephanie A, Emery, Jack, Abraham, Gilu, Pascoe, Ashlyn, Hughes, Sebastian A, Weir, Ashley, Hawkins, Edwin D, Kong, Isabella, Herold, Marco J, Pearson, Jaclyn S, Lalaoui, Najoua, Naderer, Thomas, Vince, James E, Lawlor, Kate E
• Format: Article
• Language: English
• Subjects: Apoptosis; Bacteria; BAX protein; Caspase; Cell activation; Cell death; Gonorrhea; Immune clearance; Immune response; Inflammasomes; Inflammation; Innate immunity; Lipopolysaccharides; Macrophages; Membrane vesicles; Membranes; Monocytes; Mortality; Myeloid cells; Neisseria gonorrhoeae; Pathogens; Signal transduction; Survival; Vesicles
• ISSN: 1469-221X; 1469-3178
• DOI: 10.15252/embr.202356865

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. image Cell death and inflammatory signalling crosstalk is critical for innate immune responses to pathogens. This study identifies the BCL‐2 family member A1 as a temporal regulator of these processes in myeloid cells upon bacterial recognition. LPS‐induced A1 expression in macrophages and monocytes delays apoptosis and NLRP3 inflammasome activation. Monocyte survival upon pathogen sensing is regulated by the short‐lived pro‐survival proteins MCL‐1 and A1. A1‐deficient myeloid cells can engage necroptotic signalling when apoptotic caspase activity is compromised. A1‐deficiency enhances IL‐1β responses to Neisseria gonorrhoeae ‐derived outer membrane vesicles (NOMVs).