Format

Send to

Choose Destination
Infect Immun. 2019 Jun 3. pii: IAI.00132-19. doi: 10.1128/IAI.00132-19. [Epub ahead of print]

NF-κB RelA is required for hepatoprotection during pneumonia and sepsis.

Author information

1
Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts, USA.
2
Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.
3
Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.
4
Department of Microbiology, Boston University School of Medicine, Boston, Massachusetts, USA.
5
Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts, USA.
6
Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts, USA ljquinton@bu.edu.

Abstract

Pneumonia and sepsis are distinct, but integrally linked public health concerns. The hepatic acute phase response (APR), which is largely dependent on transcription factors NF-κB RelA and STAT3, is a hallmark of these pathologies and other injurious conditions. Inactivation of the APR can promote liver injury, a frequently observed organ dysfunction during sepsis. However, whether or how the acute phase changes promote liver tissue resilience during infections are unclear. To determine the hepatoprotective role of the hepatic APR, we utilized mice bearing hepatocyte-specific deletions of either RelA or STAT3. Mice were challenged intratracheally (i.t.), intravenously (i.v.), or intraperitoneally (i.p.) with Escherichia coli, Klebsiella pneumoniae, Streptococcus pneumoniae, lipopolysaccharide (LPS), or alpha-galactosylceramide (αGalCer) to induce pneumonia, sepsis, or NKT cell activation. Liver injury was observed in RelA-null (hepRelAΔ/Δ) mice, but not STAT3-null (hepSTAT3Δ/Δ) mice during pneumonia. Absence of RelA resulted in hepatotoxicity across several models of pneumonia, sepsis, and NKT cell activation. Injury was associated with increased levels of activated caspase-3 and -8, and substantial alteration of the hepatic transcriptome. Hepatotoxicity in the absence of RelA could be reversed by neutralization of TNFα. These results indicate the requirement of RelA-dependent inducible hepatoprotection during pneumonia and sepsis. Further, results demonstrate RelA-dependent gene programs are critical for maintaining liver homeostasis against TNFα-driven immunotoxicity.

PMID:
31160364
DOI:
10.1128/IAI.00132-19

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center