Tumor Necrosis Factor-Neuropeptide Y Cross Talk Regulates Inflammation, Epithelial Barrier Functions, and Colonic Motility

• Type of Material: Article
• Authors: Bindu Chandrasekharan, Emory University; Sabrina Jeppsson, Emory University; Stefan Pienkowski, Emory University; Denise D. Belsham, University of Toronto; Shanthi V. Sitaraman, Emory University; Didier Merlin, Georgia State University; Efi Kokkotou, Harvard University; Asma Nusrat, Emory University; Malu Tansey, Emory University; Shanthi Srinivasan, Emory University
• Language: English
• Date: 2013-11-01
• Publisher: Oxford University Press (OUP): Policy B - Oxford Open Option B - CC-BY
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2013 Crohn's & Colitis Foundation of America, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1097/01.MIB.0000437042.59208.9f
• Title of Journal or Parent Work: Inflammatory Bowel Diseases
• ISSN: 1078-0998
• Volume: 19
• Issue: 12
• Start Page: 2535
• End Page: 2546
• Grant/Funding Information: This work is funded by the Crohn’s and Colitis Foundation of America Career Development Award (BC), NIH-RO1 (DK080684, SS), VA-MERIT award (SS) and DDRDC (DK064399, SS), DK06411 (SVS), DK59888 (AN) and DK080058 (EK)
• Keywords: NITRIC-OXIDE; CROHNS-DISEASE; barrier functions; EXPERIMENTAL COLITIS; enteric neurons; NERVOUS-SYSTEM; TNF-ALPHA; INTESTINAL INFLAMMATION; Gastroenterology & Hepatology; BOWEL-DISEASE; GENE-EXPRESSION; experimental colitis; Life Sciences & Biomedicine; INNATE IMMUNITY; NPY; TNF; ENTERIC NEURONS; colonic motility; Science & Technology
• Research Categories: Biology, Physiology; Health Sciences, Medicine and Surgery

Abstract

Background: Neuro-immune interactions play a significant role in regulating the severity of inflammation. Our previous work demonstrated that neuropeptide Y (NPY) is upregulated in the enteric nervous system during murine colitis and that NPY knockout mice exhibit reduced inflammation. Here, we investigated if NPY expression during inflammation is induced by tumor necrosis factor (TNF), the main proinflammatory cytokine. Methods: Using primary enteric neurons and colon explant cultures from wild type and NPY knockout (NPY-/-) mice, we determined if NPY knockdown modulates TNF release and epithelial permeability. Further, we assessed if NPY expression is inducible by TNF in enteric neuronal cells and mouse model of experimental colitis, using the TNF inhibitors-etanercept (blocks transmembrane and soluble TNF) and XPro1595 (blocks soluble TNF only). Results: We found that enteric neurons express TNF receptors (TNFR1 and R2). Primary enteric neurons from NPY-/- mice produced less TNF compared with wild type. Further, TNF activated NPY promoter in enteric neurons through phospho-c-Jun. NPY-/- mice had decreased intestinal permeability. In vitro, NPY increased epithelial permeability through phosphatidyl inositol-3-kinase (PI3-K)-induced pore-forming claudin-2. TNF inhibitors attenuated NPY expression in vitro and in vivo. TNF inhibitor-treated colitic mice exhibited reduced NPY expression and inflammation, reduced oxidative stress, enhanced neuronal survival, and improved colonic motility. XPro1595 had more protective effects on neuronal survival and motility compared with etanercept. Conclusions: We demonstrate a novel TNF-NPY cross talk that modulates inflammation, barrier functions, and colonic motility during inflammation. It is also suggested that selective blocking of soluble TNF may be a better therapeutic option than using anti-TNF antibodies.