Increased autophagic sequestration in adaptor protein-3 deficient dendritic cells limits inflammasome activity and impairs antibacterial immunity

PLoS Pathogens

Sunny Shin¹  Ariel J. Lefkovith²  Adriana R. Mantegazza³  Igor E. Brodsky³  Meghan A. Wynosky-Dolfi⁴  Michael S. Marks⁴  Cierra N. Casson⁵ 

[1] Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States of America;Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, United States of America;Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, United States of America;Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States of America;Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States of America

关键词: Inflammasomes;    Pearls;    Autophagic cell death;    Flow cytometry;    Enzyme-linked immunoassays;    Phagosomes;    Alumni;    Cytokines;   

DOI  :  10.1371/journal.ppat.1006785

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Bacterial pathogens that compromise phagosomal membranes stimulate inflammasome assembly in the cytosol, but the molecular mechanisms by which membrane dynamics regulate inflammasome activity are poorly characterized. We show that in murine dendritic cells (DCs), the endosomal adaptor protein AP-3 –which optimizes toll-like receptor signaling from phagosomes–sustains inflammasome activation by particulate stimuli. AP-3 independently regulates inflammasome positioning and autophagy induction, together resulting in delayed inflammasome inactivation by autophagy in response to Salmonella Typhimurium (STm) and other particulate stimuli specifically in DCs. AP-3-deficient DCs, but not macrophages, hyposecrete IL-1β and IL-18 in response to particulate stimuli in vitro, but caspase-1 and IL-1β levels are restored by silencing autophagy. Concomitantly, AP-3-deficient mice exhibit higher mortality and produce less IL-1β, IL-18, and IL-17 than controls upon oral STm infection. Our data identify a novel link between phagocytosis, inflammasome activity and autophagy in DCs, potentially explaining impaired antibacterial immunity in AP-3-deficient patients.

【 授权许可】

CC BY