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

Speir, M; Tye, H; Gottschalk, TA; Simpson, DS; Djajawi, TM; Deo, P; Ambrose, RL; Conos, SA; Emery, J; Abraham, G; Pascoe, A; Hughes, SA; Weir, A; Hawkins, ED; Kong, I; Herold, MJ; Pearson, JS; Lalaoui, N; Naderer, T; Vince, JE; Lawlor, KE

Author(s): Speir, M; Tye, H; Gottschalk, TA; Simpson, DS; Djajawi, TM; Deo, P; Ambrose, RL; Conos, SA; Emery, J; Abraham, G; Pascoe, A; Hughes, SA; Weir, A; Hawkins, ED; Kong, I; Herold, MJ; Pearson, JS; Lalaoui, N; Naderer, T; Vince, JE; Lawlor, KE;
Details: Publication Year 2023-11-06,Volume 24,Issue #11,Page e56865
Journal Title: EMBO Reports
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.
Publisher: EMBO Press
Keywords: Animals; Mice; *Inflammasomes/metabolism; *NLR Family, Pyrin Domain-Containing 3 Protein/genetics/metabolism; bcl-2-Associated X Protein/metabolism; Myeloid Cells/metabolism; Cell Death; Interleukin-1beta/metabolism; Bcl-2a1; Nlrp3; TLR ligation; mitochondrial apoptosis; myeloid cells
Research Division(s): Inflammation; Blood Cells And Blood Cancer
PubMed ID: 37846472
Publisher's Version: https://doi.org/10.15252/embr.202356865
Open Access at Publisher's Site: https://doi.org/10.15252/embr.202356865
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2023-11-20 12:03:40

Last Modified: 2023-11-20 12:16:41