Reduced caveolin-1 promotes hyperinflammation due to abnormal heme oxygenase-1 localization in lipopolysaccharide-challenged macrophages with dysfunctional cystic fibrosis transmembrane conductance regulator

Ping Xia Zhang, Thomas S. Murray, Valeria R. Villella, Eleonora Ferrari, Speranza Esposito, Anthony D'Souza, Valeria Raia, Luigi Maiuri, Diane S. Krause, Marie E. Egan, Emanuela M. Bruscia

Research output: Contribution to journalArticle

Abstract

We have previously reported that TLR4 signaling is increased in LPS-stimulated cystic fibrosis (CF) macrophages (MFs), contributing to the robust production of proinflammatory cytokines. The heme oxygenase-1 (HO-1)/CO pathway modulates cellular redox status, inflammatory responses, and cell survival. The HO-1 enzyme, together with the scaffold protein caveolin 1 (CAV-1), also acts as a negative regulator of TLR4 signaling in MFs. In this study, we demonstrate that in LPS-challenged CF MFs, HO-1 does not compartmentalize normally to the cell surface and instead accumulates intracellularly. The abnormal HO-1 localization in CF MFs in response to LPS is due to decreased CAV-1 expression, which is controlled by the cellular oxidative state, and is required for HO-1 delivery to the cell surface. Overexpression of HO-1 or stimulating the pathway with CO-releasing molecules enhances CAV-1 expression in CF MFs, suggesting a positive-feed forward loop between HO-1/CO induction and CAV- 1 expression. These manipulations re-established HO-1 and CAV-1 cell surface localization in CF MFs. Consistent with restoration of HO-1/CAV-1-negative regulation of TLR4 signaling, genetic or pharmacological (CO-releasing molecule 2) induced enhancement of this pathway decreased the inflammatory response of CF MFs and CF mice treated with LPS. In conclusion, our results demonstrate that the counterregulatory HO-1/CO pathway, which is critical in balancing and limiting the inflammatory response, is defective in CF MFs through a CAV-1-dependent mechanism, exacerbating the CF MF response to LPS. This pathway could be a potential target for therapeutic intervention for CF lung disease.

Original languageEnglish
Pages (from-to)5196-5206
Number of pages11
JournalJournal of Immunology
Volume190
Issue number10
DOIs
Publication statusPublished - May 15 2013

ASJC Scopus subject areas

  • Immunology

Fingerprint Dive into the research topics of 'Reduced caveolin-1 promotes hyperinflammation due to abnormal heme oxygenase-1 localization in lipopolysaccharide-challenged macrophages with dysfunctional cystic fibrosis transmembrane conductance regulator'. Together they form a unique fingerprint.

  • Cite this

    Zhang, P. X., Murray, T. S., Villella, V. R., Ferrari, E., Esposito, S., D'Souza, A., Raia, V., Maiuri, L., Krause, D. S., Egan, M. E., & Bruscia, E. M. (2013). Reduced caveolin-1 promotes hyperinflammation due to abnormal heme oxygenase-1 localization in lipopolysaccharide-challenged macrophages with dysfunctional cystic fibrosis transmembrane conductance regulator. Journal of Immunology, 190(10), 5196-5206. https://doi.org/10.4049/jimmunol.1201607