Extracellular NCOA4 is a mediator of septic death by activating the AGER-NFKB pathway.
Autophagy
; : 1-16, 2024 Jul 04.
Article
in En
| MEDLINE
| ID: mdl-38916095
ABSTRACT
Sepsis, a life-threatening condition resulting from a dysregulated response to pathogen infection, poses a significant challenge in clinical management. Here, we report a novel role for the autophagy receptor NCOA4 in the pathogenesis of sepsis. Activated macrophages and monocytes secrete NCOA4, which acts as a mediator of septic death in mice. Mechanistically, lipopolysaccharide, a major component of the outer membrane of Gram-negative bacteria, induces NCOA4 secretion through autophagy-dependent lysosomal exocytosis mediated by ATG5 and MCOLN1. Moreover, bacterial infection with E. coli or S. enterica leads to passive release of NCOA4 during GSDMD-mediated pyroptosis. Upon release, extracellular NCOA4 triggers the activation of the proinflammatory transcription factor NFKB/NF-κB by promoting the degradation of NFKBIA/IκB molecules. This process is dependent on the pattern recognition receptor AGER, rather than TLR4. In vivo studies employing endotoxemia and polymicrobial sepsis mouse models reveal that a monoclonal neutralizing antibody targeting NCOA4 or AGER delays animal death, protects against organ damage, and attenuates systemic inflammation. Furthermore, elevated plasma NCOA4 levels in septic patients, particularly in non-survivors, correlate positively with the sequential organ failure assessment score and concentrations of lactate and proinflammatory mediators, such as TNF, IL1B, IL6, and HMGB1. These findings demonstrate a previously unrecognized role of extracellular NCOA4 in inflammation, suggesting it as a potential therapeutic target for severe infectious diseases. Abbreviation BMDMs bone marrow-derived macrophages; BUN blood urea nitrogen; CLP cecal ligation and puncture; ELISA enzyme-linked immunosorbent assay; LPS lipopolysaccharide; NO nitric oxide; SOFA sequential organ failure assessment.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Language:
En
Journal:
Autophagy
Year:
2024
Document type:
Article
Affiliation country:
China
Country of publication:
Estados Unidos