The prolyl isomerase Pin1 acts as a novel molecular switch for TNF-α-induced priming of the NADPH oxidase in human neutrophils

Tarek Boussetta, Marie Anne Gougerot-Pocidalo, Gilles Hayem, Silvia Ciappelloni, Houssam Raad, Riad Arabi Derkawi, Odile Bournier, Yolande Kroviarski, Xiao Zhen Zhou, James S. Malter, Ping K. Lu, Aghleb Bartegi, Pham My Chan Dang, Jamel El-Benna

Research output: Contribution to journalArticlepeer-review

62 Scopus citations

Abstract

Neutrophils play a key role in host defense by releasing reactive oxygen species (ROS). However, excessive ROS production by neutrophil nicotinamide adenine dinucleotide phosphate (NADPH) oxidase can damage bystander tissues, thereby contributing to inflammatory diseases. Tumor necrosis factor-α (TNF-α), a major mediator of inflammation, does not activate NADPH oxidase but induces a state of hyperresponsiveness to subsequent stimuli, an action known as priming. The molecular mechanisms by which TNF-α primes the NADPH oxidase are unknown. Here we show that Pin1, a unique cis-trans prolyl isomerase, is a previously unrecognized regulator of TNF-a-induced NADPH oxidase hyperactivation. We first showed that Pin1 is expressed in neutrophil cytosol and that its activity is markedly enhanced by TNF-a. Inhibition of Pin1 activity with juglone or with a specific peptide inhibitor abrogated TNF-α-induced priming of neutrophil ROS production induced by N-formylmethionyl-leucyl- phenylalanine peptide (fMLF). TNF-α enhanced fMLF-induced Pin1 and p47phox translocation to the membranes and juglone inhibited this process. Pin1 binds to p47phox via phosphorylated Ser345, thereby inducing conformational changes that facilitate p47phox phosphorylation on other sites by protein kinase C. These findings indicate that Pin1 is critical for TNF-α-induced priming of NADPH oxidase and for excessive ROS production. Pin1 inhibition could potentially represent a novel anti-inflammatory strategy.

Original languageEnglish (US)
Pages (from-to)5795-5802
Number of pages8
JournalBlood
Volume116
Issue number26
DOIs
StatePublished - Dec 23 2010

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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