CD1d-restricted pathways in hepatocytes control local natural killer T cell homeostasis and hepatic inflammation

Invariant natural killer T (iNKT) cells recognize lipid antigens presented by CD1d and play a central role in regulating immunity and inflammation in peripheral tissues. However, the mechanisms which govern iNKT cell homeostasis after thymic emigration are incompletely understood. Here we demonstrate that microsomal triglyceride transfer protein (MTP), a protein involved in the transfer of lipids onto CD1d, regulates liver iNKT cell homeostasis in a manner dependent on hepatocyte CD1d. Mice with hepatocyte-specific loss of MTP exhibit defects in the function of CD1d and show increased hepatic iNKT cell numbers as a consequence of altered iNKT cell apoptosis. Similar findings were made in mice with hepatocyte-specific loss of CD1d confirming a critical role of CD1d in this process. Moreover, increased hepatic iNKT cell abundance in the absence of MTP is associated with susceptibility to severe iNKT cell-mediated hepatitis thus demonstrating the importance of CD1d-dependent control of liver iNKT cells in maintaining immunological homeostasis in the liver. Together, these data demonstrate an unanticipated role of parenchymal cells, as shown here for hepatocytes, in tissue-specific regulation of CD1d-restricted immunity and further suggest that alterations in lipid metabolism may affect iNKT cell homeostasis through effects on CD1d-associated lipid antigens.Work was supported by: The Deutsche Forschungsgemeinschaft (DFG) (ZE814/5-1), the European Research Council (ERC Starting Grant agreement n°336528), the Crohn’s and Colitis Foundation of America (Postdoctoral Fellowship Award), the European Commission (Marie Curie International Reintegration Grant n°256363), and the DFG Excellence Clusters “Inflammation at Interfaces” and “Center for Regenerative Therapies ” (S.Z.) and NIH grants DK044319, DK051362, DK053056, DK088199 and the Harvard Digestive Diseases Center (HDDC) (DK0034854) (R.S.B.)

Epithelial endoplasmic reticulum stress orchestrates a protective IgA response.

Immunoglobulin A (IgA) is the major secretory immunoglobulin isotype found at mucosal surfaces, where it regulates microbial commensalism and excludes luminal factors from contacting intestinal epithelial cells (IECs). IgA is induced by both T cell-dependent and -independent (TI) pathways. However, little is known about TI regulation. We report that IEC endoplasmic reticulum (ER) stress induces a polyreactive IgA response, which is protective against enteric inflammation. IEC ER stress causes TI and microbiota-independent expansion and activation of peritoneal B1b cells, which culminates in increased lamina propria and luminal IgA. Increased numbers of IgA-producing plasma cells were observed in healthy humans with defective autophagy, who are known to exhibit IEC ER stress. Upon ER stress, IECs communicate signals to the peritoneum that induce a barrier-protective TI IgA response.Wellcome Trust Senior Investigator Award 106260/Z/14/Z HORIZON2020/European Research Council Consolidator Grant 64888

Vanin-1 and its role in intestinal inflammation

Les cellules épithéliales produisent des facteurs influençant la réponse inflammatoire intestinale. L'étude de la contribution de ces facteurs à l'homéostasie des tissus est devenue essentielle à la compréhension des maladies inflammatoires chroniques intestinales (MICIs). Vanin-1 est une enzyme épithéliale qui produit des facteurs solubles dans les tissus dont l'intestin en réponse à un stress. Nous avons identifié Vanin-1 comme facteur de susceptibilité et marqueur des MICIs chez l'homme. La création d'une souris mutante nous a permis d'identifier des mécanismes d'action potentiels de Vanin-1 dans les tissus. Vanin-1 pourrait un jour être exploité pour développer une stratégie thérapeutique contre les MICIs.Intestinal epithelial cells have recently been identified as producing factors influencing grandly the curse of intestinal inflammation. It became of a great importance, therefore, to identify the contribution of epithelial molecules to inflammatory bowel diseases (IBD). Vanin-1 is an epithelial enzymes which release soluble factors in tissues such as gut. This study identifies Vanin-1 as a marker and a susceptibility factor of IBD. By producing a mutant mice, we identified potential mechanisms by which Vanin-1 could act in tissues. It is hoped that Vnn1 can be exploited to develop future therapeutic strategies against IBD

Epithelial endoplasmic reticulum stress orchestrates a protective IgA response

Immunoglobulin A (IgA) is the major secretory immunoglobulin isotype found at mucosal surfaces, where it regulates microbial commensalism and excludes luminal factors from contacting intestinal epithelial cells (IECs). IgA is induced by both T cell-dependent and -independent (TI) pathways. However, little is known about TI regulation. We report that IEC endoplasmic reticulum (ER) stress induces a polyreactive IgA response, which is protective against enteric inflammation. IEC ER stress causes TI and microbiota-independent expansion and activation of peritoneal B1b cells, which culminates in increased lamina propria and luminal IgA. Increased numbers of IgA-producing plasma cells were observed in healthy humans with defective autophagy, who are known to exhibit IEC ER stress. Upon ER stress, IECs communicate signals to the peritoneum that induce a barrier-protective TI IgA response

Functional Polymorphisms in the Regulatory Regions of the VNN1 Gene Are Associated with Susceptibility to Inflammatory Bowel Diseases

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