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

Abstract

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.

The Anti-tumoral Properties of Orexin/Hypocretin Hypothalamic Neuropeptides: An Unexpected Therapeutic Role

“…Bar = 50 μm for (A, B C, E, F) ; Bar = 100 μm for (D) . The sources of graphs were based on Voisin et al ( 44 ), Dayot et al ( 46 ), and Messal et al ( 56 ).…”

“…In ulcerative colitis (UC) and pancreatitis, OX1R was highly expressed in inflamed areas (Figure 3 ). Moreover, OxA was able to induce an anti-inflammatory effect in mice models reproducing UC or pancreatitis ( 56 , 102 ). A recent study indicates a higher prevalence of immunopathological diseases, including purpura, multiple sclerosis, systemic lupus erythematosus, psoriasis, Crohn's disease, or ulcerative colitis, in narcoleptic patients ( 103 ).…”

Systemic administration of orexin A ameliorates established experimental autoimmune encephalomyelitis by diminishing neuroinflammation

“…In addition, peripheral administration of orexin A by a subcutaneous osmotic pump improved the survival of mice to lipopolysaccharide (LPS)-induced endotoxin shock, decreasing the levels of multiple proinflammatory cytokines and chemokines [6]. Recently, it has been shown that orexin A exhibited anti-inflammatory actions in a murine model of experimental colitis by inhibiting the NF-kB pathway [7]. In vitro studies using the microglial cell line BV2 suggest that orexin A may directly inhibit innate immune responses.…”

Orexin-A Exerts Equivocal Role in Atherosclerosis Process Depending on the Duration of Exposure: In Vitro Study

“…Herein, we demonstrated that short-term incubation (6 h) of HAECs with orexin-A causes a dose-dependent decrease in MCP-1 gene with a significant reduction at the higher concentration. Messal et al, using an animal model of ulcerative colitis, have demonstrated the anti-inflammatory effects of orexin-A via decreasing the expression of pro-inflammatory cytokines, amongst them MCP-1 in immune cells, an effect mediated by OX1R [9]. Similar effects of orexin-A on MCP-1 expression have been reported by Fatemi et al using an animal model of experimental autoimmune encephalomyelitis (EAE) [10].…”

“…Of interest, in vitro, as well as, animal studies have shown the anti-inflammatory effects of orexin-A on cells and tissues involved in various diseases, such as multiple sclerosis, ulcerative colitis etc. ; these effects are exerted via either inhibiting the synthesis and secretion of pro-inflammatory cytokines, or inducing the synthesis of anti-inflammatory cytokines and mediated via orexin receptors orexin-A receptor 1 (OX1R) and orexin-A receptor 2 (OX2R) [8][9][10].…”