Eicosanoid-Activated PPARα Inhibits NFκB-Dependent Bacterial Clearance During Post-Influenza Superinfection

Secondary bacterial infection (superinfection) post influenza is a serious clinical complication often leading to pneumonia and death. Eicosanoids are bioactive lipid mediators that play critical roles in the induction and resolution of inflammation. CYP450 lipid metabolites are anti-inflammatory li...

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Published in:Frontiers in cellular and infection microbiology Vol. 12; p. 881462
Main Authors: Lucarelli, Ronald, Gorrochotegui-Escalante, Norma, Taddeo, Jessica, Buttaro, Bettina, Beld, Joris, Tam, Vincent
Format: Journal Article
Language:English
Published: Lausanne Frontiers Media SA 04.07.2022
Frontiers Media S.A
Subjects:
Antibacterial activity
Bacterial infections
Cellular and Infection Microbiology
Cytochrome P450
eicosanoid
Eicosanoids
Inflammation
Influenza
innate immunity
lipidomic
Lipids
Macrophages
Metabolites
Mortality
NF-κB protein
Nuclear transport
Phosphorylation
Staphylococcus aureus
Superinfection
Toll-like receptors
Transcription activation
ISSN:2235-2988, 2235-2988
Online Access:Get full text
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Summary:Secondary bacterial infection (superinfection) post influenza is a serious clinical complication often leading to pneumonia and death. Eicosanoids are bioactive lipid mediators that play critical roles in the induction and resolution of inflammation. CYP450 lipid metabolites are anti-inflammatory lipid mediators that are produced at an excessive level during superinfection potentiating the vulnerability to secondary bacterial infection. Using Nanostring nCounter technology, we have defined the targeted transcriptional response where CYP450 metabolites dampen the Toll-like receptor signaling in macrophages. CYP450 metabolites are endogenous ligands for the nuclear receptor and transcription factor, PPARα. Activation of PPARα hinders NFκB p65 activities by altering its phosphorylation and nuclear translocation during TLR stimulation. Additionally, activation of PPARα inhibited anti-bacterial activities and enhanced macrophage polarization to an anti-inflammatory subtype (M2b). Lastly, Ppara –/– mice, which are partially protected in superinfection compared to C57BL/6 mice, have increased lipidomic responses and decreased M2-like macrophages during superinfection.
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This article was submitted to Microbes and Innate Immunity, a section of the journal Frontiers in Cellular and Infection Microbiology
Edited by: Charles Robert Brown, University of Missouri, United States
Reviewed by: Maria Salagianni, Biomedical Research Foundation of the Academy of Athens (BRFAA), Greece; Larisa Labzin, The University of Queensland, Australia
ISSN:2235-2988
2235-2988
DOI:10.3389/fcimb.2022.881462