Vanin molecules participate to tissue response to stress and code for pantetheinase providing the thiol-containing metabolite cysteamine to tissues. Mice lacking the Vanin-1 isoform lack cysteamine and show increased resistance to inflammation-triggered gut damage. In contrast, the absence of cysteamine is associated with defective epithelial cytoprotection in diabetes. We explore the relations existing between cysteamine-driven inflammation versus cytoprotection in vivo and in human pathologies.
Vanin-1 an epithelial pantetheinase regulating inflammation
Vanin-1 codes for pantetheinase which provides cysteamine to tissues. Mice lacking Vanin-1 are protected from acute inflammation triggered by toxic or infectious insults in gut. In contrast these mice poorly develop organized granulomas in response to infection by intracellular bacteria. This suggests that Vanin-1 expressed by epithelial cells exerts a control on immune responses.
Vanin-1 is cytoprotective
Using a mutant diabetes prone NOD mice lacking Vanin-1, we showed that cysteamine exerts a cytoprotective role on pancreatic islets and thus Vanin-1 deficiency is detrimental in type 1 diabetes. These results indicate that whereas Vanin-1 is an essential regulator of inflammation following an acute stress, it also participates to tissue cytoprotection in more chronic diseases. This epithelial molecule senses tissue stress and licenses downstream activation of innate immune responses.
Mechanism of cysteamine action
As a thiol-containing metabolite, cysteamine is suspected to engage disulfide bridges with target molecules. We identified two pathways on which cysteamine acts in vivo. Firstly, the oxidized form of cysteamine inhibits glutathione synthesis therefore regulating glutathione levels in tissues. This mechanism might account for the extent of tissue damage upon stress but also contributes to normal chondrogenesis by regulating chondroblast expansion.
Secondly, Vanin-1 behaves as a PPARg antagonist in vivo. Since PPARg is essential in dampening inflammation in colon, Vanin-1 may exert its proinflammatory activity in part throug PPARg inhibition.
Another pantetehinase isoform exists in mouse and is encoded by the Vanin-3 gene showing distinct tissue specificity. We are currently exploring its role in immune cell activation.
Vanin in human diseases
The last aspect of our work is to document involvement of Vanin molecules in human inflammatory diseases with a specific emphasis on inflammatory bowel diseases. We have developed new tools to explore VNN1 expression in human tissues and completed a first global analysis of VNN expression and function in tissues from patients. These results open new perspectives on the use of modulators of pantetheinase activity in the handling of inflammatory diseases in man.