Skip to main content

PPARα exacerbates necroptosis, leading to increased mortality in postinfluenza bacterial superinfection.

Citation
Tam, V. C., et al. “Pparα Exacerbates Necroptosis, Leading To Increased Mortality In Postinfluenza Bacterial Superinfection.”. Proceedings Of The National Academy Of Sciences Of The United States Of America, pp. 15789-15798.
Center UCSD-UCLA
Author Vincent C Tam, Rosa Suen, Piper M Treuting, Aaron Armando, Ronald Lucarelli, Norma Gorrochotegui-Escalante, Alan H Diercks, Oswald Quehenberger, Edward A Dennis, Alan Aderem, Elizabeth S Gold
Keywords PPARα, influenza, necroptosis, superinfection, systems biology
Abstract

Patients infected with influenza are at high risk of secondary bacterial infection, which is a major proximate cause of morbidity and mortality. We have shown that in mice, prior infection with influenza results in increased inflammation and mortality upon infection, recapitulating the human disease. Lipidomic profiling of the lungs of superinfected mice revealed an increase in CYP450 metabolites during lethal superinfection. These lipids are endogenous ligands for the nuclear receptor PPARα, and we demonstrate that mice are less susceptible to superinfection than wild-type mice. PPARα is an inhibitor of NFκB activation, and transcriptional profiling of cells isolated by bronchoalveolar lavage confirmed that influenza infection inhibits NFκB, thereby dampening proinflammatory and prosurvival signals. Furthermore, network analysis indicated an increase in necrotic cell death in the lungs of superinfected mice compared to mice infected with alone. Consistent with this, we observed reduced NFκB-mediated inflammation and cell survival signaling in cells isolated from the lungs of superinfected mice. The kinase RIPK3 is required to induce necrotic cell death and is strongly induced in cells isolated from the lungs of superinfected mice compared to mice infected with alone. Genetic and pharmacological perturbations demonstrated that PPARα mediates RIPK3-dependent necroptosis and that this pathway plays a central role in mortality following superinfection. Thus, we have identified a molecular circuit in which infection with influenza induces CYP450 metabolites that activate PPARα, leading to increased necrotic cell death in the lung which correlates with the excess mortality observed in superinfection.

Year of Publication
2020
Journal
Proceedings of the National Academy of Sciences of the United States of America
Volume
117
Issue
27
Number of Pages
15789-15798
Date Published
12/2020
ISSN Number
1091-6490
DOI
10.1073/pnas.2006343117
Alternate Journal
Proc Natl Acad Sci U S A
PMID
32581129
PMCID
PMC7355019
Download citation