Ectopic expression of OX1R in ulcerative colitis mediates anti-inflammatory effect of orexin-A

• Published in: Biochimica et biophysica acta. Molecular basis of disease Vol. 1864; no. 11; pp. 3618 - 3628
• Main Authors: Messal, N., Fernandez, N., Dayot, S., Gratio, V., Nicole, P., Prochasson, C., Chantret, I., LeGuilloux, G., Jarry, A., Couvelard, A., Tréton, X., Voisin, T., Ogier-Denis, E., Couvineau, A.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-11-2018; Elsevier
• Subjects: Adult; Animals; Cancer; Cell Line; Colitis, Ulcerative - chemically induced; Colitis, Ulcerative - drug therapy; Colitis, Ulcerative - immunology; Colitis, Ulcerative - pathology; Cytokines - immunology; Cytokines - metabolism; Dextran Sulfate - toxicity; Disease Models, Animal; Down-Regulation; Ectopic Gene Expression; Epithelial Cells - drug effects; Epithelial Cells - immunology; Epithelial Cells - metabolism; Epithelial Cells - pathology; Female; GPCR; Humans; Inflammation; Inflammatory bowel disease; Intestinal Mucosa - drug effects; Intestinal Mucosa - immunology; Intestinal Mucosa - pathology; Life Sciences; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Neuropeptide; NF-kappa B - immunology; NF-kappa B - metabolism; Orexin Receptor Antagonists - pharmacology; Orexin Receptors - genetics; Orexin Receptors - metabolism; Orexins; Orexins - pharmacology; Orexins - therapeutic use; Phenylurea Compounds - pharmacology; Retrospective Studies; Signal Transduction - drug effects; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Ulcerative colitis; Young Adult; Inflammatory bowel disease; GPCR; Inflammation; Orexins; Neuropeptide; Ulcerative colitis
• DOI: 10.1016/j.bbadis.2018.08.023
• EISSN: 1879-260X
• ISSN: 0925-4439

Orexins (orexin-A and orexin-B) are hypothalamic peptides that are produced by the same precursor and are involved in sleep/wake control, which is mediated by two G protein-coupled receptor subtypes, OX1R and OX2R. Ulcerative colitis (UC) is an inflammatory bowel disease, (IBD) which is characterized by long-lasting inflammation and ulcers that affect the colon and rectum mucosa and is known to be a significant risk factor for colon cancer development. Based on our recent studies showing that OX1R is aberrantly expressed in colon cancer, we wondered whether orexin-A could play a role in UC. Immunohistochemistry studies revealed that OX1R is highly expressed in the affected colonic epithelium of most UC patients, but not in the non-affected colonic mucosa. Injection of exogenous orexin-A specifically improved the inflammatory symptoms in the two colitis murine models. Conversely, injection of inactive orexin-A analog, OxB7–28 or OX1R specific antagonist SB-408124 did not have anti-inflammatory effect. Moreover, treatment with orexin-A in DSS-colitis induced OX1R−/− knockout mice did not have any protective effect. The orexin-A anti-inflammatory effect was due to the decreased expression of pro-inflammatory cytokines in immune cells and specifically in T-cells isolated from colonic mucosa. Moreover, orexin-A inhibited canonical NFκB activation in an immune cell line and in intestinal epithelial cell line. These results suggest that orexin-A might represent a promising alternative to current UC therapies.
•OX1R is highly expressed in human colonic mucosa from UC patients.•Injection of orexin-A improves inflammation symptoms in two murine.•Orexin-A down-regulates the pro-inflammatory cytokine production by immune cells isolated from colonic mucosa.•Orexin-A inhibits IL-8 secretion in immune cell line and in intestinal epithelial cell line.