| First Author | Zhang PX | Year | 2013 |
| Journal | J Immunol | Volume | 190 |
| Issue | 10 | Pages | 5196-206 |
| PubMed ID | 23606537 | Mgi Jnum | J:202542 |
| Mgi Id | MGI:5519999 | Doi | 10.4049/jimmunol.1201607 |
| Citation | Zhang PX, et al. (2013) 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 190(10):5196-206 |
| abstractText | We have previously reported that TLR4 signaling is increased in LPS-stimulated cystic fibrosis (CF) macrophages (MPhis), 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 MPhis. In this study, we demonstrate that in LPS-challenged CF MPhis, HO-1 does not compartmentalize normally to the cell surface and instead accumulates intracellularly. The abnormal HO-1 localization in CF MPhis 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 MPhis, 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 MPhis. 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 MPhis 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 MPhis through a CAV-1-dependent mechanism, exacerbating the CF MPhi response to LPS. This pathway could be a potential target for therapeutic intervention for CF lung disease. |
