The inhibitory effects of vitamin D on colitis have been previously documented. Global vitamin D receptor (VDR) deletion exaggerates colitis, but the relative anticolitic contribution of epithelial and nonepithelial VDR signaling is unknown. Here, we showed that colonic epithelial VDR expression was substantially reduced in patients with Crohn’s disease or ulcerative colitis. Moreover, targeted expression of human VDR (hVDR) in intestinal epithelial cells (IECs) protected mice from developing colitis. In experimental colitis models induced by 2,4,6-trinitrobenzenesulfonic acid, dextran sulfate sodium, or CD4+CD45RBhi T cell transfer, transgenic mice expressing hVDR in IECs were highly resistant to colitis, as manifested by marked reductions in clinical colitis scores, colonic histological damage, and colonic inflammation compared with WT mice. Reconstitution of
Weicheng Liu, Yunzi Chen, Maya Aharoni Golan, Maria L. Annunziata, Jie Du, Urszula Dougherty, Juan Kong, Mark Musch, Yong Huang, Joel Pekow, Changqing Zheng, Marc Bissonnette, Stephen B. Hanauer, Yan Chun Li
Cholecystokinin (CCK) is a satiety hormone produced by discrete enteroendocrine cells scattered among absorptive cells of the small intestine. CCK is released into blood following a meal; however, the mechanisms inducing hormone secretion are largely unknown. Ingested fat is the major stimulant of CCK secretion. We recently identified a novel member of the lipoprotein remnant receptor family known as immunoglobulin-like domain containing receptor 1 (ILDR1) in intestinal CCK cells and postulated that this receptor conveyed the signal for fat-stimulated CCK secretion. In the intestine, ILDR1 is expressed exclusively in CCK cells. Orogastric administration of fatty acids elevated blood levels of CCK in wild-type mice but not
Rashmi Chandra, Yu Wang, Rafiq A. Shahid, Steven R. Vigna, Neil J. Freedman, Rodger A. Liddle
Cystic fibrosis (CF) pigs develop disease with features remarkably similar to those in people with CF, including exocrine pancreatic destruction, focal biliary cirrhosis, micro-gallbladder, vas deferens loss, airway disease, and meconium ileus. Whereas meconium ileus occurs in 15% of babies with CF, the penetrance is 100% in newborn CF pigs. We hypothesized that transgenic expression of porcine CF transmembrane conductance regulator (
David A. Stoltz, Tatiana Rokhlina, Sarah E. Ernst, Alejandro A. Pezzulo, Lynda S. Ostedgaard, Philip H. Karp, Melissa S. Samuel, Leah R. Reznikov, Michael V. Rector, Nicholas D. Gansemer, Drake C. Bouzek, Mahmoud H. Abou Alaiwa, Mark J. Hoegger, Paula S. Ludwig, Peter J. Taft, Tanner J. Wallen, Christine Wohlford-Lenane, James D. McMenimen, Jeng-Haur Chen, Katrina L. Bogan, Ryan J. Adam, Emma E. Hornick, George A. Nelson IV, Eric A. Hoffman, Eugene H. Chang, Joseph Zabner, Paul B. McCray Jr., Randall S. Prather, David K. Meyerholz, Michael J. Welsh
Chronic pancreatitis is an inflammatory disease that causes progressive destruction of pancreatic acinar cells and, ultimately, loss of pancreatic function. We investigated the role of IκB kinase α (IKKα) in pancreatic homeostasis. Pancreas-specific ablation of IKKα (
Ning Li, Xuefeng Wu, Ryan G. Holzer, Jun-Hee Lee, Jelena Todoric, Eek-Joong Park, Hisanobu Ogata, Anna S. Gukovskaya, Ilya Gukovsky, Donald P. Pizzo, Scott VandenBerg, David Tarin, Çiǧdem Atay, Melek C. Arkan, Thomas J. Deerinck, Jorge Moscat, Maria Diaz-Meco, David Dawson, Mert Erkan, Jörg Kleeff, Michael Karin
After cell fate specification, differentiating cells must amplify the specific subcellular features required for their specialized function. How cells regulate such subcellular scaling is a fundamental unanswered question. Here, we show that the E3 ubiquitin ligase Mindbomb 1 (MIB1) is required for the apical secretory apparatus established by gastric zymogenic cells as they differentiate from their progenitors. When
Benjamin J. Capoccia, Ramon U. Jin, Young-Yun Kong, Richard M. Peek Jr., Matteo Fassan, Massimo Rugge, Jason C. Mills
A highly complex network of intrinsic enteric neurons is required for the digestive and homeostatic functions of the gut. Nevertheless, the genetic and molecular mechanisms that regulate their assembly into functional neuronal circuits are currently unknown. Here we report that the planar cell polarity (PCP) genes
Valentina Sasselli, Werend Boesmans, Pieter Vanden Berghe, Fadel Tissir, André M. Goffinet, Vassilis Pachnis
Cell therapy has the potential to treat gastrointestinal motility disorders caused by diseases of the enteric nervous system. Many studies have demonstrated that various stem/progenitor cells can give rise to functional neurons in the embryonic gut; however, it is not yet known whether transplanted neural progenitor cells can migrate, proliferate, and generate functional neurons in the postnatal bowel in vivo. We transplanted neurospheres generated from fetal and postnatal intestinal neural crest–derived cells into the colon of postnatal mice. The neurosphere-derived cells migrated, proliferated, and generated neurons and glial cells that formed ganglion-like clusters within the recipient colon. Graft-derived neurons exhibited morphological, neurochemical, and electrophysiological characteristics similar to those of enteric neurons; they received synaptic inputs; and their neurites projected to muscle layers and the enteric ganglia of the recipient mice. These findings show that transplanted enteric neural progenitor cells can generate functional enteric neurons in the postnatal bowel and advances the notion that cell therapy is a promising strategy for enteric neuropathies.
Ryo Hotta, Lincon A. Stamp, Jaime P.P. Foong, Sophie N. McConnell, Annette J. Bergner, Richard B. Anderson, Hideki Enomoto, Donald F. Newgreen, Florian Obermayr, John B. Furness, Heather M. Young
Acid sphingomyelinase (ASM) regulates the homeostasis of sphingolipids, including ceramides and sphingosine-1-phosphate (S1P). These sphingolipids regulate carcinogenesis and proliferation, survival, and apoptosis of cancer cells. However, the role of ASM in host defense against liver metastasis remains unclear. In this study, the involvement of ASM in liver metastasis of colon cancer was examined using
Yosuke Osawa, Atsushi Suetsugu, Rie Matsushima-Nishiwaki, Ichiro Yasuda, Toshiji Saibara, Hisataka Moriwaki, Mitsuru Seishima, Osamu Kozawa
N-formyl peptide receptors (FPRs) are critical regulators of host defense in phagocytes and are also expressed in epithelia. FPR signaling and function have been extensively studied in phagocytes, yet their functional biology in epithelia is poorly understood. We describe a novel intestinal epithelial FPR signaling pathway that is activated by an endogenous FPR ligand, annexin A1 (ANXA1), and its cleavage product Ac2-26, which mediate activation of ROS by an epithelial NADPH oxidase, NOX1. We show that epithelial cell migration was regulated by this signaling cascade through oxidative inactivation of the regulatory phosphatases PTEN and PTP-PEST, with consequent activation of focal adhesion kinase (FAK) and paxillin. In vivo studies using intestinal epithelial specific Nox1–/–IEC and AnxA1–/– mice demonstrated defects in intestinal mucosal wound repair, while systemic administration of ANXA1 promoted wound recovery in a NOX1-dependent fashion. Additionally, increased ANXA1 expression was observed in the intestinal epithelium and infiltrating leukocytes in the mucosa of ulcerative colitis patients compared with normal intestinal mucosa. Our findings delineate a novel epithelial FPR1/NOX1-dependent redox signaling pathway that promotes mucosal wound repair.
Giovanna Leoni, Ashfaqul Alam, Philipp-Alexander Neumann, J. David Lambeth, Guangjie Cheng, James McCoy, Roland S. Hilgarth, Kousik Kundu, Niren Murthy, Dennis Kusters, Chris Reutelingsperger, Mauro Perretti, Charles A. Parkos, Andrew S. Neish, Asma Nusrat
Intestinal barrier function requires intricate cooperation between intestinal epithelial cells and immune cells. Enteropathogens are able to invade the intestinal lymphoid tissue known as Peyer’s patches (PPs) and disrupt the integrity of the intestinal barrier. However, the underlying molecular mechanisms of this process are poorly understood. In mice infected with Yersinia pseudotuberculosis, we found that PP barrier dysfunction is dependent on the Yersinia virulence plasmid and the expression of TLR-2 by hematopoietic cells, but not by intestinal epithelial cells. Upon TLR-2 stimulation, Y. pseudotuberculosis–infected monocytes activated caspase-1 and produced IL-1β. In turn, IL-1β increased NF-κB and myosin light chain kinase activation in intestinal epithelial cells, thus disrupting the intestinal barrier by opening the tight junctions. Therefore, Y. pseudotuberculosis subverts intestinal barrier function by altering the interplay between immune and epithelial cells during infection.
Camille Jung, Ulrich Meinzer, Nicolas Montcuquet, Elodie Thachil, Danielle Château, Raphaële Thiébaut, Maryline Roy, Ziad Alnabhani, Dominique Berrebi, Monique Dussaillant, Eric Pedruzzi, Sophie Thenet, Nadine Cerf-Bensussan, Jean-Pierre Hugot, Frederick Barreau