NF-κB RelA Is Required for Hepatoprotection during Pneumonia and Sepsis

Yuri Kim; Eri Allen; Lillia A Baird; Elise M Symer; Filiz T Korkmaz; Elim Na; Christine V Odom; Matthew R Jones; Joseph P Mizgerd; Katrina E Traber; Lee J Quinton

doi:10.1128/IAI.00132-19

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NF-κB RelA Is Required for Hepatoprotection during Pneumonia and Sepsis

Journal article

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NF-κB RelA Is Required for Hepatoprotection during Pneumonia and Sepsis

Yuri Kim, Eri Allen, Lillia A Baird, Elise M Symer, Filiz T Korkmaz, Elim Na, Christine V Odom, Matthew R Jones, Joseph P Mizgerd, Katrina E Traber, …

Infection and immunity, Vol.87(8), e00132

08/01/2019

DOI: 10.1128/IAI.00132-19

PMCID: PMC6652780

PMID: 31160364

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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 is 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 , , , lipopolysaccharide (LPS), or alpha-galactosylceramide (αGalCer) to induce pneumonia, sepsis, or NKT cell activation. Liver injury was observed in RelA-null (hepRelA ) mice but not STAT3-null (hepSTAT3 ) mice during pneumonia. The 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 tumor necrosis factor alpha (TNF-α). These results indicate the requirement of RelA-dependent inducible hepatoprotection during pneumonia and sepsis. Further, the results demonstrate that RelA-dependent gene programs are critical for maintaining liver homeostasis against TNF-α-driven immunotoxicity.

Acute-Phase Reaction

Animals

Apoptosis

Chemokine CCL2 - physiology

Kupffer Cells - physiology

Liver - pathology

Mice

Mice, Inbred C57BL

Natural Killer T-Cells - immunology

Pneumonia - pathology

Sepsis - pathology

STAT3 Transcription Factor - physiology

Transcription Factor RelA - physiology

Tumor Necrosis Factor-alpha - physiology

Details

Title: Subtitle: NF-κB RelA Is Required for Hepatoprotection during Pneumonia and Sepsis
Creators: Yuri Kim - Boston University
Eri Allen - Boston University
Lillia A Baird - Boston University School of Medicine
Elise M Symer - Boston University
Filiz T Korkmaz - Boston University
Elim Na - Boston University
Christine V Odom - Boston University
Matthew R Jones - Boston University
Joseph P Mizgerd - Boston University
Katrina E Traber - Boston University
Lee J Quinton - Boston University
Resource Type: Journal article
Publication Details: Infection and immunity, Vol.87(8), e00132
DOI: 10.1128/IAI.00132-19
PMID: 31160364
PMCID: PMC6652780
NLM abbreviation: Infect Immun
ISSN: 0019-9567
eISSN: 1098-5522
Grant note: R01 AI115053 / NIAID NIH HHS R01 HL111449 / NHLBI NIH HHS R35 HL135756 / NHLBI NIH HHS R01 GM120060 / NIGMS NIH HHS T32 HL007035 / NHLBI NIH HHS UL1 TR001430 / NCATS NIH HHS F31 HL134205 / NHLBI NIH HHS
Language: English
Date published: 08/01/2019
Academic Unit: Microbiology and Immunology
Record Identifier: 9984696653102771

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