Front Immunol . Influenza virus causes lung immunopathology through down-regulating PPARγ activity in macrophages

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Front Immunol


. 2022 Aug 25;13:958801.
doi: 10.3389/fimmu.2022.958801. eCollection 2022.
Influenza virus causes lung immunopathology through down-regulating PPARγ activity in macrophages


Hongbo Zhang ¹ , Taylor Alford ² , Shuangquan Liu ^{1 3} , Dongming Zhou ⁴ , Jieru Wang ^{1 2}



Affiliations

• PMID: 36091002
• PMCID: PMC9452838
• DOI: 10.3389/fimmu.2022.958801

Abstract

Fatal influenza (flu) virus infection often activates excessive inflammatory signals, leading to multi-organ failure and death, also referred to as cytokine storm. PPARγ (Peroxisome proliferator-activated receptor gamma) agonists are well-known candidates for cytokine storm modulation. The present study identified that influenza infection reduced PPARγ expression and decreased PPARγ transcription activity in human alveolar macrophages (AMs) from different donors. Treatment with PPARγ agonist Troglitazone ameliorated virus-induced proinflammatory cytokine secretion but did not interfere with the IFN-induced antiviral pathway in human AMs. In contrast, PPARγ antagonist and knockdown of PPARγ in human AMs further enhanced virus-stimulated proinflammatory response. In a mouse model of influenza infection, flu virus dose-dependently reduced PPARγ transcriptional activity and decreased expression of PPARγ. Moreover, PPARγ agonist troglitazone significantly reduced high doses of influenza infection-induced lung pathology. In addition, flu infection reduced PPARγ expression in all mouse macrophages, including AMs, interstitial macrophages, and bone-marrow-derived macrophages but not in alveolar epithelial cells. Our results indicate that the influenza virus specifically targets the PPARγ pathway in macrophages to cause acute injury to the lung.

Keywords: PPARγ; PPARγ agonist; acute lung injury; influenza; lung macrophage.