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Intra-tracheal Administration of Haemophilus influenzae in Mouse Models to Study Airway Inflammation
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Eicosanoid-Activated PPARα Inhibits NFκB-Dependent Bacterial Clearance During Post-Influenza Superinfection

Ronald Lucarelli1, Norma Gorrochotegui-Escalante1, Jessica Taddeo1

  • 1Center for Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States.

Frontiers in Cellular and Infection Microbiology
|July 21, 2022
PubMed

Insights

During influenza superinfections, excessive CYP450 lipid metabolites dampen immune responses, increasing vulnerability. These metabolites activate PPARα, inhibiting antibacterial activity and promoting anti-inflammatory macrophages.

Area of Science:

  • Immunology
  • Metabolism
  • Molecular Biology

Background:

  • Secondary bacterial infections post-influenza are a major cause of mortality.
  • Eicosanoids and CYP450 lipid metabolites are key regulators of inflammation.
  • Excessive CYP450 metabolites during superinfection exacerbate host vulnerability.

Purpose of the Study:

  • To investigate the role of CYP450 metabolites in modulating immune responses during influenza superinfection.
  • To define the transcriptional response to CYP450 metabolites in macrophages.
  • To elucidate the mechanism by which CYP450 metabolites affect Toll-like receptor (TLR) signaling and macrophage polarization.

Main Methods:

  • Nanostring nCounter technology for transcriptional profiling.
  • Analysis of PPARα activation and its downstream effects on NFκB signaling.
  • Assessment of macrophage polarization (M2b subtype).
  • Studies using Ppara knockout mice during superinfection models.

Main Results:

  • CYP450 metabolites were found to dampen TLR signaling in macrophages.
  • These metabolites act as endogenous ligands for PPARα, inhibiting NFκB p65 activity.
  • PPARα activation suppressed antibacterial activities and promoted M2b anti-inflammatory macrophage polarization.
  • Ppara-/- mice showed partial protection against superinfection, with altered lipidomic profiles and reduced M2-like macrophages.

Conclusions:

  • CYP450 metabolites play a significant role in immune dysregulation during influenza superinfection.
  • PPARα activation by these metabolites contributes to increased susceptibility by impairing antibacterial defenses and promoting immunosuppression.
  • Targeting the CYP450-PPARα axis may offer therapeutic strategies for secondary bacterial infections post-influenza.
Keywords:
Cytochrome P450Staphylococcus aureusSuperinfectioneicosanoidinfluenzainnate immunitylipidomic

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