Targeted Deletion of Neuropeptide Y (NPY) Modulates Experimental Colitis

Abstract

BackgroundNeurogenic inflammation plays a major role in the pathogenesis of inflammatory bowel disease (IBD). We examined the role of neuropeptide Y (NPY) and neuronal nitric oxide synthase (nNOS) in modulating colitis.MethodsColitis was induced by administration of dextran sodium sulphate (3% DSS) or streptomycin pre-treated Salmonella typhimurium (S.T.) in wild type (WT) and NPY (NPY−/−) knockout mice. Colitis was assessed by clinical score, histological score and myeloperoxidase activity. NPY and nNOS expression was assessed by immunostaining. Oxidative stress was assessed by measuring catalase activity, glutathione and nitrite levels. Colonic motility was assessed by isometric muscle recording in WT and DSS-treated mice.ResultsDSS/S.T. induced an increase in enteric neuronal NPY and nNOS expression in WT mice. WT mice were more susceptible to inflammation compared to NPY−/− as indicated by higher clinical & histological scores, and myeloperoxidase (MPO) activity (p<0.01). DSS-WT mice had increased nitrite, decreased glutathione (GSH) levels and increased catalase activity indicating more oxidative stress. The lower histological scores, MPO and chemokine KC in S.T.-treated nNOS−/− and NPY−/−/nNOS−/− mice supported the finding that loss of NPY-induced nNOS attenuated inflammation. The inflammation resulted in chronic impairment of colonic motility in DSS-WT mice. NPY –treated rat enteric neurons in vitro exhibited increased nitrite and TNF-α production.ConclusionsNPY mediated increase in nNOS is a determinant of oxidative stress and subsequent inflammation. Our study highlights the role of neuronal NPY and nNOS as mediators of inflammatory processes in IBD.

Increased Susceptibility of Melanin-Concentrating Hormone-Deficient Mice to Infection with Salmonella enterica Serovar Typhimurium

“…While we describe here that MCH-deficient mice developed a more-disseminated Salmonella infection which was associated with increased mortality under the conditions tested (Fig. 1), mice deficient for NPY or neurokinin-1 (the preferred substance P receptor) were found to be protected and to develop attenuated disease compared to their wild-type littermates (22,23).…”

Neuropeptides and the Microbiota-Gut-Brain Axis

“…Specifically, NPY is able to promote colonic inflammation, an effect that is supported by several lines of evidence: (i) NPY knockout mice are largely resistant to the induction of dextran sulfate sodium-induced colitis [93,94].…”

“…The antiinflammatory phenotype of Y1 receptor knockout mice results from a defect in antigen-presenting cell function, a reduction of TNF-alpha and IL-12 production by macrophages, and a decrease in the number of effector T cells [90]. Furthermore, experimentally induced colitis is associated with an increase in the colonic synthesis of NPY [93,95,97], a reduction of colonic Y1 receptor expression and a loss of the antisecretory action of NPY in the colon [98]. In contrast, the colonic levels of the related gut hormone PYY are decreased in rats with DSSinduced colitis [99].…”

Neuro-Immune Networks in Gastrointestinal Disorders

“…Therefore, the anti- or pro-inflammatory effect of NPY is dependent on Y receptor subtypes and its specific expression in certain immune cell subtypes [32]. In the context of colitis, NPY antisense oligodeoxynucleotide attenuated DSS colitis in the rat [38] and the genetic deletion of NPY decreased the severity of DSS colitis in mice [39]. Moreover, Y1-deficient mice were protected in DSS colitis [40].…”