Reduced Caveolin-1 Promotes Hyperinflammation due to Abnormal Heme Oxygenase-1 Localization in Lipopolysaccharide-Challenged Macrophages with Dysfunctional Cystic Fibrosis Transmembrane Conductance Regulator

Abstract

We have previously reported that TLR4 signaling is increased in lipopolysaccharide (LPS) -stimulated Cystic Fibrosis (CF) macrophages (MΦs), contributing to the robust production of pro-inflammatory cytokines. The heme oxygenase (HO-1)/carbon monoxide (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. Here, 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 (CORM2)enhancesCAV-1 expression in CF MΦs, suggesting a positive-feed forward loop between HO-1/CO induction and CAV-1 expression. These manipulations reestablished HO-1 and CAV-1 cell surface localization in CF MΦ's. Consistent with restoration of HO-1/CAV-1 negative regulation of TLR4 signaling, genetic or pharmacological (CORM2)-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 counter-regulatory 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's response to LPS. This pathway could be a potential target for therapeutic intervention for CF lung disease.

Increased susceptibility of Cftr−/− mice to LPS-induced lung remodeling

“…mice resulted in a similar lung hyperinflammatory response (8,36). Together, these data suggest that the hyperinflammatory response to acute inflammatory challenges and extensive lung remodeling with chronic inflammation are driven by lack of functional CFTR independent of the class of mutation: null mutations, which are mimicked by the Cftr Ϫ/Ϫ mouse, or class 2 mutations (F508del/F508del).…”

Curcumin prevents diabetic nephropathy against inflammatory response via reversing caveolin-1 Tyr14 phosphorylation influenced TLR4 activation

“…Recently, cav-1 has also been implicated as a modulator of inflammation and innate immunity [19,[39][40][41]. It is reported that cav-1 phosphorylation at Tyr 14 following LPS exposure induced the interaction of cav-1 and TLR4, thereby, TLR4 activation of MyD88, leading to the activation of NF-κB and generation of pro-inflammatory cytokines [19].…”

“…It is reported that cav-1 phosphorylation at Tyr 14 following LPS exposure induced the interaction of cav-1 and TLR4, thereby, TLR4 activation of MyD88, leading to the activation of NF-κB and generation of pro-inflammatory cytokines [19]. In murine macrophages, cav-1 bound to TLR4 inhibited LPS-induced proinflammatory cytokine (IL-6, IL1β and TNF-α) production [18,41,42], indicating that a cav-1 binding motif in TLR4 is essential for the attenuation of pro-inflammatory signaling. It was reported that TLR4 highly colocalized with cav-1 in caveolae (rafts) fractions in peritoneal macrophages [18] and in human aortic endothelial cells [43].…”

Inflammation in cystic fibrosis lung disease: Pathogenesis and therapy

“…Macrophages with dysfunctional CFTR show delayed phagolysomal fusion and bacterial clearance after ingestion of Burkhoderia cepacia [52]. CF macrophages also display decreased caveolin-1 expression and enhanced TLR4-dependent responses to LPS [53]. Finally, CFTR deficiency has been reported to induce an intrinsic predisposition of naïve T lymphocytes to differentiate towards a Th17 phenotype [41].…”