[Show abstract][Hide abstract] ABSTRACT: Colitis involves immune cell–mediated tissue injuries, but the contribution of epithelial cells remains largely unclear. Vanin-1 is an epithelial ectoenzyme with a pantetheinase activity that provides cysteamine/cystamine to tissue. Using the 2,4,6-trinitrobenzene sulfonic acid (TNBS)-colitis model we show here that Vanin-1 deficiency protects from colitis. This protection is reversible by administration of cystamine or bisphenol A diglycidyl ether, a peroxisome proliferator-activated receptor (PPAR)
후 antagonist. We further demonstrate that Vanin-1, by antagonizing PPAR 후, licenses the production of inflammatory mediators by intestinal epithelial cells. We propose that Vanin-1 is an epithelial sensor of stress that exerts a dominant control over innate immune responses in tissue. Thus, the Vanin-1/ pantetheinase activity might be a new target for therapeutic intervention in infl
ammatory bowel disease.
Journal of Experimental Medicine 01/2007; 203(13):2817-27. DOI:10.1084/jem.20061640 · 12.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Q fever is caused by Coxiella burnetii, a bacterium that survives in MPhi. Vanin-1 is a membrane-anchored pantetheinase that controls tissue inflammation. Consequently, Vanin-1-deficient mice represent a unique mouse model in which stress-induced inflammation is limited by the reaction of resident tissue cells. To investigate the contribution of host tissues in the control of a bacterial infection, we infected Vanin-1-deficient mice with C. burnetii. Mortality and morbidity of mice were not affected. The lack of Vanin-1 had no effect on C. burnetii clearance but decreased the formation of granulomas in spleen and liver. Granuloma formation depends upon MPhi recruitment and activation in these tissues. Whereas the former was slightly impaired in mutant mice, the lack of Vanin-1 significantly affected the activation pattern of BM-derived MPhi stimulated by C. burnetii. While their microbicidal activity against C. burnetii was moderately impaired, they exhibited decreased inducible nitric oxide synthase (iNOS) and MCP-1 gene expression, and increased IL-10 and arginase expression. In liver from mutant mice, increased arginase expression and decreased expression of MCP-1 and iNOS were reminiscent of MPhi data. These results suggest a role of Vanin-1 in granuloma formation in response to C. burnetii by skewing MPhi activation toward an M2 program.
European Journal of Immunology 01/2007; 37(1):24-32. DOI:10.1002/eji.200636054 · 4.03 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Vanin-1 is an epithelial ectoenzyme with pantetheinase activity and generating the amino-thiol cysteamine through the metabolism of pantothenic acid (vitamin B(5)). Here we show that Vanin-1(-/-) mice, which lack cysteamine in tissues, exhibit resistance to oxidative injury induced by whole-body gamma-irradiation or paraquat. This protection is correlated with reduced apoptosis and inflammation and is reversed by treating mutant animals with cystamine. The better tolerance of the Vanin-1(-/-) mice is associated with an enhanced gamma-glutamylcysteine synthetase activity in liver, probably due to the absence of cysteamine and leading to elevated stores of glutathione (GSH), the most potent cellular antioxidant. Consequently, Vanin-1(-/-) mice maintain a more reducing environment in tissue after exposure to irradiation. In normal mice, we found a stress-induced biphasic expression of Vanin-1 regulated via antioxidant response elements in its promoter region. This process should finely tune the redox environment and thus change an early inflammatory process into a late tissue repair process. We propose Vanin-1 as a key molecule to regulate the GSH-dependent response to oxidative injury in tissue at the epithelial level. Therefore, Vanin/pantetheinase inhibitors could be useful for treatment of damage due to irradiation and pro-oxidant inducers.