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

J Immunol. 2013 May 15;190(10):5196-206. doi: 10.4049/jimmunol.1201607. Epub 2013 Apr 19.


We have previously reported that TLR4 signaling is increased in LPS-stimulated cystic fibrosis (CF) macrophages (MΦs), 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 MΦs. In this study, we demonstrate that in LPS-challenged CF MΦs, HO-1 does not compartmentalize normally to the cell surface and instead accumulates intracellularly. The abnormal HO-1 localization in CF MΦs 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 MΦs, 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 MΦs. 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 MΦs 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 MΦs through a CAV-1-dependent mechanism, exacerbating the CF MΦ response to LPS. This pathway could be a potential target for therapeutic intervention for CF lung disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Animals
  • Caveolin 1 / biosynthesis
  • Caveolin 1 / metabolism*
  • Cells, Cultured
  • Child
  • Child, Preschool
  • Cystic Fibrosis / immunology
  • Cystic Fibrosis / metabolism
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics
  • Cystic Fibrosis Transmembrane Conductance Regulator / immunology
  • Cystic Fibrosis Transmembrane Conductance Regulator / metabolism*
  • Female
  • Heme Oxygenase-1 / biosynthesis
  • Heme Oxygenase-1 / metabolism*
  • Humans
  • Inflammation / immunology
  • Lipopolysaccharides / immunology
  • Lung Diseases / immunology
  • Lung Diseases / metabolism
  • Macrophages / immunology*
  • Macrophages / metabolism*
  • Male
  • Membrane Proteins / biosynthesis
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Knockout
  • Nasal Polyps
  • Reactive Oxygen Species / metabolism
  • Signal Transduction
  • Toll-Like Receptor 4 / metabolism
  • Young Adult


  • Caveolin 1
  • Lipopolysaccharides
  • Membrane Proteins
  • Reactive Oxygen Species
  • TLR4 protein, human
  • Toll-Like Receptor 4
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Heme Oxygenase-1