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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 M\u03a6s. In this study, we demonstrate that in LPS-challenged CF M\u03a6s, HO-1 does not compartmentalize normally to the cell surface and instead accumulates intracellularly. The abnormal HO-1 localization in CF M\u03a6s 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 M\u03a6s, 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 M\u03a6s. Consistent with restoration of HO-1\/CAV-1\u2013negative regulation of TLR4 signaling, genetic or pharmacological (CO-releasing molecule 2) induced enhancement of this pathway decreased the inflammatory response of CF M\u03a6s 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 M\u03a6s through a CAV-1\u2013dependent mechanism, exacerbating the CF M\u03a6 response to LPS. This pathway could be a potential target for therapeutic intervention for CF lung disease.<\/jats:p>","DOI":"10.4049\/jimmunol.1201607","type":"journal-article","created":{"date-parts":[[2013,4,20]],"date-time":"2013-04-20T03:35:28Z","timestamp":1366428928000},"page":"5196-5206","source":"Crossref","is-referenced-by-count":54,"title":["Reduced Caveolin-1 Promotes Hyperinflammation due to Abnormal Heme Oxygenase-1 Localization in Lipopolysaccharide-Challenged Macrophages with Dysfunctional Cystic Fibrosis Transmembrane Conductance Regulator"],"prefix":"10.1093","volume":"190","author":[{"given":"Ping-Xia","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Yale University School of Medicine , New Haven, CT 06509"},{"name":"Laboratory Medicine, Yale University School of Medicine , New Haven, CT 06509"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas S","family":"Murray","sequence":"additional","affiliation":[{"name":"Laboratory Medicine, Yale University School of Medicine , New Haven, CT 06509"},{"name":"Department of Basic Sciences, Frank H. Netter School of Medicine, Quinnipiac University , Hamden, CT 06518"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria R","family":"Villella","sequence":"additional","affiliation":[{"name":"Division of Genetics and Cell Biology, European Institute for Research in Cystic Fibrosis, San Raffaele Scientific Institute , Milan 20132,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleonora","family":"Ferrari","sequence":"additional","affiliation":[{"name":"Division of Genetics and Cell Biology, European Institute for Research in Cystic Fibrosis, San Raffaele Scientific Institute , Milan 20132,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Speranza","family":"Esposito","sequence":"additional","affiliation":[{"name":"Division of Genetics and Cell Biology, European Institute for Research in Cystic Fibrosis, San Raffaele Scientific Institute , Milan 20132,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony","family":"D\u2019Souza","sequence":"additional","affiliation":[{"name":"Laboratory Medicine, Yale University School of Medicine , New Haven, CT 06509"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Raia","sequence":"additional","affiliation":[{"name":"Cystic Fibrosis Unit, Department of Pediatrics, Federico II University , Naples 80131,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luigi","family":"Maiuri","sequence":"additional","affiliation":[{"name":"Division of Genetics and Cell Biology, European Institute for Research in Cystic Fibrosis, San Raffaele Scientific Institute , Milan 20132,","place":["Italy"]},{"name":"Institute of Pediatrics, University of Foggia , Foggia 71100,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diane S","family":"Krause","sequence":"additional","affiliation":[{"name":"Laboratory Medicine, Yale University School of Medicine , New Haven, CT 06509"},{"name":"Cell Biology, Yale University School of Medicine , New Haven, CT 06509"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie E","family":"Egan","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Yale University School of Medicine , New Haven, CT 06509"},{"name":"Cellular and Molecular Physiology, Yale University School of Medicine , New Haven, CT 06509"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emanuela M","family":"Bruscia","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Yale University School of Medicine , New Haven, CT 06509"},{"name":"Division of Genetics and Cell Biology, European Institute for Research in Cystic Fibrosis, San Raffaele Scientific Institute , Milan 20132,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2013,5,15]]},"reference":[{"key":"2025032407005774600_r1","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1164\/rccm.200505-840OE","article-title":"Cystic fibrosis since 1938","volume":"173","author":"Davis","year":"2006","journal-title":"Am. 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